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PED2001 Flashcards

1
Q

What are the two processes that determine drug concentrations

A
  • translocation of drug molecules
  • chemical transformation
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2
Q

how do drugs move around the body

A
  • bulk flow (in the bloodstream)
  • diffusional transfer (molecule by molecule over short distances)
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3
Q

why does diffusional transfer differ with the chemical nature of the drug

A
  • hydrophobic diffusion barrier
  • aqueous diffusion
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4
Q

what is a compartmentalised body

A
  • body made of interconnected compartments separated by cell membranes
  • the ability of drugs and other chemicals to move between these compartments depends on the selectivity of the membranes and the chemical properties of the drug
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5
Q

what is the vascular endothelium

A
  • acts as a filter (cut off MW 80-100k)
  • the gaps between cells are filled with a protein matrix - tight packed - this acts as MW filter
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6
Q

why is the endothelium discontinuous in liver and spleens

A
  • large fenestrations allows drugs to exchange freely between blood and interstitium in the liver
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7
Q

what is the structure of endothelial cell in liver

A
  • endothelium
  • basement membrane
  • slit junctions
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8
Q

structure of CNS and placenta

A
  • astrocyte foot processes - lipophilic barriers
  • tight junctions
  • slit junctions
  • basement membrane
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9
Q

what is the importance of the structure of the barriers in CNS and placenta

A
  • charged drugs cannot move through
  • lipid soluble and carrier mediated transport can be used to move from plasma to CNS
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10
Q

how can drugs be transferred across cell membranes

A
  • diffusing direct through lipid
  • diffusing through aqueous pores - most drugs are too big to move through
  • combination with a transmembrane carrier protein
  • pinocytosis (for macromolecules e.g. insulin
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11
Q

how do drugs diffuse through lipid

A
  • non-polar substances dissolve readily in non-polar solvents - cell membranes are lipid-rich environments
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12
Q

how is permeability coefficient determined

A
  • the number of molecules crossing the membrane per unit area of time (J)
  • concentration difference across the membrane (delta C)
  • J = P x delta C
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13
Q

what are the physiochemical factors contributing to permeability

A
  • partition coefficient
  • diffusion coefficient
  • diffusion coefficient is equal to 1/square root MW
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14
Q

what is the relationship between lipid solubility and permeability

A
  • close correlation between lipid solubility and permeability of cell membrane to different substances
  • lipid solubility an important determinant of pharmacokinetic characteristics of a drug
  • rate of absorption from the gut, penetration into brain and other tissues, and extent of renal elimination can be predictable
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15
Q

how is pH and ionisation involved in absorption

A
  • ionised drug formed are much less able to penetrate cell membranes
  • ratio of charged drug/uncharged drug concentrations is determined by the pH of the compartment
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16
Q

how is lipid solubility involved in absorption

A
  • the lipid solubility of uncharged species AH or B depend on the chemical nature of the drug
  • for many drugs the uncharged species is sufficiently lipid soluble (except e.g. aminoglycosides0
  • bases are neutral and absorbed easily
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17
Q

what does ionisation effect

A
  • drug permeability across membranes
  • ionised drugs show reduced permeability
  • steady state distribution of drug molecules between aqueous compartments, in the presence of a pH mechanism
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18
Q

what is the pH partition mechanism

A
  • qualitative effects of pH changes in different body compartments on the pharmacokinetic of weak acids and bases
  • but its not the main determinants of drug absorption from the GI tract
  • small intestine has hugely greater surface area of absorption compared to stomach
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19
Q

why does aspirin absorption vary

A
  • aspirin absorption increased by metoclopramide and decreased by propantheline
  • ionised forms are not totally impermeable
  • body compartments are rarely at equilibrium in real life
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20
Q

what are the consequences of the pH partition mechanism

A
  • urinary acidification increases excretion of weak bases and decreased that of weak acids
  • urinary alkalisation decreases excretion of weak bases and increases that of weak acids
  • increases plasma pH (e.g. sodium bicarbonate) causes extraction of weakly acidic drugs from CNS into plasma
  • decreases plasma pH (e.g. acetazolamide) causes weakly acidic drugs to accumulate in the CNS
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21
Q

what is the structure of the nephron

A
  • distal tubule collecting duct (control Na and H2O balance)
  • glomerulus (renal blood flow filtration
  • loop of hence (urinary concentration
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22
Q

how does urinary alkalinisation increase excretion of aspirin

A
  • at normal urinary pH, a proportion of salicylate is unionised and can be absorbed back into the systemic circulation in the nephron
  • when urine is alkaline, salicylate is charged, so reabsorption is much reduced
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23
Q

what is carrier mediated transport

A
  • transport of physiologically important molecules in and out of cells (e.g. sugars, amino acids, neurotransmitters and metal ions)
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24
Q

what are the examples of carrier mediated transport

A
  • passive transport - move molecules in direction of electrochemical gradient
  • active transport - movement against an electrochemical gradient coupled to an energy source
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25
Q

what are the properties of carrier mediated transport

A
  • saturable
  • can be inhibited
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26
Q

why is renal handling of cisplatin important

A
  • cisplatin is very nephrotoxic because it is efficiently taken up into the proximal tubule, but rate of secretion is lower
  • higher exposure results in destruction of mitochondria - proximal tubular cell death
  • organic solutes lost to urine increased Na loss increases H2O loss - falcon syndrome
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27
Q

what are the carried mediated transport systems

A
  • levodopa - transported by the carrier responsible for phenylalanine
  • fluorouracil - transported by carrier for natural pyrimidine - thymine and uracil
  • iron - carrier system in jejunum
  • calcium - vitamine D dépendent carrier system
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28
Q

where in the body are carrier mediated transporters essential

A
  • the renal tubule
  • the biliary tract
  • the blood brain barrier
    -the GI tracts
  • p-glycoprotein - transporter responsible for MDRa
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29
Q

where else are carrier mediated transporters present

A
  • renal tubular brush border
  • membranes, in bile canaliculi, in astrocyte foot processes in brain micro vessels and in GI tracts
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30
Q

what are the other factors affecting drug pharmacokinetics (distribution and elimination)

A
  • binding to plasma protein
  • partition into body fat and other tissues
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31
Q

what are the routes of drug administration

A

oral
sublingual
rectal
application to other epithelial surface (e.g. skin, cornea vagina and nasal mucosa)
inhalation
injection

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32
Q

what are the types of injection

A

subcutaneous
intramuscular
intravenous
intrathecal

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33
Q

factors affecting GI absorption of drugs

A

GI motility
splanchnic blood flow
particle size and formulation
physiochemical factors

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34
Q

what does gastrointestinal motility have an effect on

A

migraine, diabetic neuropathy
malabsorption states and GI diseases
coeliac disease
drugs
food

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35
Q

how does coeliac disease effect gastrointestinal motility

A
  • thyroxine anddigoxin absorption decreased
  • propranolol, cotrimoxazole and cephalexin absorption increased
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36
Q

what are the physiochemical factors that effect drug GI absorption

A
  • tetracycline and calcium ions
  • bile acid binding resins (e.g. cholestyramine) interact with warfarin, thyroxin
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37
Q

what are the drugs not absorbed GI

A
  • vancomycine (used for treatment of pseudomembranous colitis caused by clostridium difficile)
  • mesalazine (a formulation of 5-aminosalicyclic acid) for treatment of crohns disease)
  • olsalazine (a dimer of two 5-aminosalicyclic acid) cleaved by colonic bacteria
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38
Q

what is systemic availability

A

the amount of drug that reaches systemic circulation intact

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39
Q

what does the rate of systemic availability rely on

A
  • pharmaceutical factors
  • gastrointestinal absorption
  • pre systemic metabolism relatively unimportant
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40
Q

what does the extent of systemic availability depend on

A

both the extent of absorption and the extent of pre-systemic metabolism

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41
Q

what is cutaneous drug administration

A
  • skin allows permeation of drugs from topically applied creams and ointments in quantities sufficient to produce systemic action
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42
Q

what are the problems with transdermal drug delivery

A
  • variability in drug administration through skin
  • resulting in lack of precision regarding the real dose absorbed
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43
Q

what are the therapeutic objectives of transdermal delivery

A
  • lack of drug dosage a characteristic of topically applied ointment and creams
  • ointments containing nitroglycerin require multiple applications per day
  • variable amount and duration of drug input
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44
Q

why is there variable amount and duration of transdermal drugs

A
  • differences in the area of skin covered with ointment
  • thickness of the ointment layer applied
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45
Q

what are the new topical dosage forms

A
  • delivery drugs to the blood stream at defined rates over prolonged period of time
  • design emphasis on control of systemic input residing in the dosage form rather than in the skin
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46
Q

why is transdermal therapy particularly suitable for the rate controlled administration

A
  • as potent, non-irritating, non-allergenic agents with suitable physiochemical properties whose current administration causes some problems
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47
Q

what are some of problems of ointments

A
  • troublesome side effects or unreliable therapeutic action with repetitive dosing with conventional dosage forms
  • patient compliance difficulaties
  • need for frequent dosing in conventional dosage forms because of the drugs short biological half life
  • gastric irritations with oral therapy
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48
Q

what is the scopolamine system

A
  • application to skin
  • drug diffusion in the direction of concentration gradient
  • energy source (the difference in the drugs chemical potential between the reservoir and the systems exterior)
  • constancy of rate delivered assured as long as drug present in excess in reservoir
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49
Q

what is intravenous drug administration

A
  • fastest and most certain route
  • single bolus injection with high concentration of drugs
  • peak drug concentration reaching tissues is critically dependent on the rate of injection
  • steady IV infusion avoids high peak plasma concentrations (e.g. lignocaine, propofol, diazepam)
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50
Q

what is the benefits of subcutaneous and intramuscular drug injections

A

SC and IM injections usually produce faster effects than oral administration

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51
Q

what does the rate of absorption of SC and IM injections depend on

A
  • the site of injection
  • local blood flow
  • drug formulations
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52
Q

what are intrathecal injections

A

injections into subarachnoid space via a lumbar puncture

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53
Q

what are the examples of intrathecal injections

A
  • methotrexate for treatments of childhood leukaemia
  • local anaesthetics (e.g. bupivacaine)
  • opiate analgesics
  • baclofen - for treatments of muscle spasm cause by chronic neurological disease
  • some antibiotics (ahminoglycosides) - treatments of nervous system infection
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54
Q

what diseases require drug administration by inhalation

A

asthma
bronchitis emphysema
lung cancer
respiratory diseases

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55
Q

why are drugs administered by inhalation

A

rapid action - rapid delivery across mucous membranes of the respiratory tract and pulmonary epithelium
minimise systemic absorption
minimise side effects (beta-agonists, glucocorticoids

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56
Q

what is asthma

A
  • inflammation (swelling)
  • mucus production (snot)
  • bronchospasm (muscle tightness)
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57
Q

what are the symptoms of asthma

A
  • shortness of breath
  • wheezing
  • tightness in the chest
  • coughing at night or after physical activity
  • waking at night with asthma symptoms
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58
Q

what are the indoor triggers of asthma

A

strong smells
cockroaches
smoke
dusty mites
furry friends
colds
mould

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59
Q

what are the outdoor triggers for asthma

A

cold/hot weather
car exhaust
pollens
exercise
mowed lawn
air pollution
grilling

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60
Q

How to treat the symptoms of asthma

A
  • adrenergic agonists (bronchodilators) and glucocorticoids (usually by inhalation)
  • beta agonists (e.g. pirbuterol, terbutalines, albuterol and salmeterol)
  • relax airway smooth muscle directly
  • provide relief for 4-6hours
  • little stimulation of alpha or beta1 receptors
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61
Q

what is the mechanism of action of glucocorticoids

A
  • inhaled glucocorticoids reduce/eliminate the use of oral glucocorticoids
  • no direct effect on airway smooth muscle
  • decrease the number and activity of cells involved in airway inflammation
  • prolonged inhalation of steroid reduced hyper-responsiveness of the airway smooth muscle
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62
Q

what are the pharmacokinetics of inhaled drugs

A
  • a large fraction deposited in the mouth and pharynx or swallowed
  • many of the clinically useful corticosteroids (e.g. beclomethasone, triamcilonone) undergo extensive 1st pass metabolism
  • therefore a small amount reaches the systemic circulation which minimises adverse effects
  • 10-20% of inhaled dose reaches the airway
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63
Q

what is theophylline

A
  • a potent bronchodilators
  • narrow therapeutic window
  • overdosing can lead to seizures and cardiac arrhythmias
  • interact with many other prescribed drugs
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64
Q

what are the other inhaled drugs for treatment of asthma

A
  • sodium cromoglycate and nedocromil sodium
  • effective prophylactic anti-inflammatory agents
  • but not useful in managing acute attacks of asthma - not direct bronchodilators
  • theophylline
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65
Q

what is the main benefit of prolonged release inhalation formulations

A
  • current formulations have short duration of clinical effects therefore advantageous to prolong pharmacological effect
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66
Q

what factors affect bioavailability of drugs

A
  • the rate of disintegration of the tablet
  • the rate of dissolution of the drug particles in the intestinal fluid
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67
Q

what are the physical factors affecting pharmaceutical availability

A
  • tablet compression and excipients - affect the rate of tablet disintegration
  • other tablet excipients - affect interaction with aqueous GI juices
  • the form of the drug e.g. crystalline or salt form
  • particle size - smaller drug particles dissolve more quickly
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68
Q

what is bioequivalence

A
  • two formulations of a drug are bioequivalent if they show comparable bioavailability and similar times to achieve peak plasma concentrations
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69
Q

what is bioinequivalence

A
  • two formulations of a drug with a significant difference in bioavailability are said to be bioinequivalent
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70
Q

what is therapeutic equivalence

A

two similar drugs are therapeutically equivalent if they have comparable efficacy and safety

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71
Q

what is the importance of alterations in pharmaceutical availability

A
  • important for drugs with narrow therapeutic index
  • switch from a formulation of low pharmaceutical availability to a formulation of high pharmaceutical availability
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72
Q

what are the determining factors for route of administration of drug

A
  • therapeutic objective (slow or fast onset of action)
  • properties of the drug
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73
Q

how can we control insulin absorption

A
  • physical state - crystalline or non-crystalline
  • the zinc or protein content
  • the nature and pH of the buffer suspension
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74
Q

what are the types of subcutaneous injections of insulin

A
  • insulin BP - soluble and amorphous - rapid onset and short duration of action
  • ultralente insulin (large crystals of insulin and high zinc content - suspended in a solution of sodium acetate/sodium chloride - onset of action approx. 7hrs and duration of action of 36hrs
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75
Q

what are the examples where the vehicle in which the drug is suspended can affect the drug diffusion rate

A
  • the absorption of drug from IM injection site may be retarded by the use of thick oils which slow down diffusion
  • vasopressin tannate in oil - diabetes insidious
  • fluphenazine decanoate in oil - schizophrenia
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76
Q

what are the examples where plasma drug concentrations differ between IM and oral dosing of the same drug

A
  • phenytoin - plasma drug concentrations after IM injections are half of those after oral dosing
  • chloramphenicol - also poorly absorbed after IM injection
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77
Q

what is the relation between diabetes insidious and lack of ADH (vasopressin)

A
  • ADH (vasopressin) inserts water pores into collecting duct membrane to enable re-absorption of solute-free water from the collecting duct into the systemic circulation
  • vasopressin binds to membrane receptor
  • receptor activates cAMP (second messenger system)
  • cell inserts AQP2 water pores into apical membrane
  • water is absorbed by osmosis into the blood
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78
Q

why are local injections used

A
  • some formulations of local anaesthetics contain adrenaline
  • vasoconstriction at site of injection
  • prevent the drug to be carried away by circulation from site of injection
  • prolongs the effect of local anaesthetic
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79
Q

why use sublingual, buccal, rectal and transdermal formulations

A
  • avoidance of 1st pass metabolism - resulting in rapid therapeutic effect
  • corticosteroids can be given by the rectal route for direct effect on the large bowel
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80
Q

what is the example of the benefit of avoidance of 1st pass metabolism

A
  • glyceryl trinitrate 10x less of dose required for therapeutic effect compared to local dosing
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81
Q

what are the step that allow corticosteroids to be given by the rectal route

A
  • drug administration via transdermal patches
  • controlled release of small amount of drug over a period of time
  • e.g. glyceryl trinitrate, hyoscine, oestradiol
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82
Q

what are the benefits of controlled release of drug

A
  • reduce the risk of gastric erosions - e.g. quinidine
  • ideal for drugs with short duration of action e.g. theophylline and nifedipine
  • unconventional formulations are not always useful e.g. beta-antagonists show good duration of effect from conventional formulation
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83
Q

what is the criteria that needs to be met for combination products in oral therapy

A
  • the frequency of administration of the two drugs is the same
  • the fixed doses in the combination product are therapeutically and optimally effective
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84
Q

what are the potential advantages of combination formulations

A
  • improved compliance
  • ease of administration
  • synergistic or additive effect
  • decreased adverse effects
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85
Q

What is an example of improve compliance

A
  • antituberculous drugs (rifampicin and isoniazid)
  • ferrous sulphate and folate acid (pregnancy)
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86
Q

what is an example of ease of administration

A

triple vaccine (diphtheria, tetanus, pertussis)

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87
Q

what are the examples of synergistic or additive effect

A
  • e.g. trimethoprim and sulphonamides (e.g. co-trioxazole)
  • amoxycillin and clavulanic acid (co-amoxiclav)
  • aspirin and codeine (simples analgesia)
  • paracetamol and metoclopramide (migraine)
  • combines oral contraceptives (oestrogen and progesterone)
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88
Q

what is the example of decreased adverse effects

A
  • e.g. -dopa and decarboxylase inhibitors (Parkinson’s)
  • diuretics (potassium-wasting and potassium sparing)
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89
Q

what are the types of special drug delivery systems

A
  • biologically erodible microspheres - loaded with drugs
  • pro drugs - cyclophosphamide, levodopa, zidovudine
  • antibody-drug conjugates - cancer chemotherapy
  • packaging in liposomes
  • gene therapy - viral vector for gene delivery
  • implantable devices
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90
Q

when are special drug delivery systems used in clinical application

A
  • brentuximab vedotin - directed to the protein CD30, which is expressed in classical Hodgkins lymphoma
  • trastuzumab emptansine (Herceptin) - binds to the HER2/neu receptor - treatment of HER2-positive metastatic breast cancer
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91
Q

what is packaging in liposomes

A
  • phospholipids loaded with non-lipid soluble drugs
  • reticuloendothelial cells in the liver - also concentrated in malignant tumours - selective delivery
  • e.g. amphotericin - treatments of mycosis - less nephrotoxic and better tolerated
  • Pfizer SARS cov2 vaccine - mRNA packaged in liposome
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92
Q

what is drug distribution

A

process by which a drug reversibly leaves the bloodstream and enters the interstitial (extracellular fluid) and/or the cells of the tissues

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93
Q

what does the delivery of a drug from plasma to the interstitial depend on

A
  • blood flow
  • capillary permeability
  • the degree of binding of the drug to plasma and tissue protein
  • the relative hydrophobicity of the drug
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94
Q

what does blood flow to tissue capillaries depend on

A

blood flow to tissue capillaries varied widely as a consequence of unequal cardiac output to various organs

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95
Q

what is the direction of blood flow to the organs

A
  • blood flow to the brain, liver, kidney –> skeletal muscle –> adipose tissue
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96
Q

what does capillary permeability depend on

A
  • capillary structure
  • drug structure
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97
Q

what is the capillary structure

A

large fenestrations allow drugs to exchange freely between blood and interstitium in the liver

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98
Q

how do drugs interact with blood-brain barrier

A
  • drugs must pass through the endothelial cells of the capillaries of CNS or be actively transported e.g. levodopa
  • lipid soluble drugs readily penetrate the CNS
  • ionised or polar drugs unable to pass through the endothelial cells of the CNS
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99
Q

how does hydrophobicity affect drug movement

A
  • hydrophobic drugs readily cross cell membranes
  • major factor in distribution of hydrophobic drug is blood flow to the area
  • hydrophilic drugs must go through slit junction
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100
Q

what are the characteristics of binding drugs to proteins

A
  • reversible binding to plasma proteins sequesters drugs in non-diffusible form
  • binding it non-selective as to chemical structure
  • binding sites for drugs similar to those for bilirubin
  • plasma albumin conjugate –> free drug –> metabolism –> excretion
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101
Q

what is volume of distribution

A
  • Vd is a hypothetical volume of fluid into which the drugs is disseminated
  • has no physiological or physical basis
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102
Q

what is the plasma compartment

A
  • drug has a large MW or binds extensively to plasma protein
  • too large to move out through slit junctions of capillaries therefore drug trapped within the plasma compartment
  • Vd = plasma water
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103
Q

how does the low molecular impact drug movement

A
  • drug has a low MW but is hydrophilic
  • moves through slit junctions into interstitial fluid
  • unable to cross lipid membrane of cells and enter intracellular fluid
  • Vd = sum of plasma water and extracellular fluid volume
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104
Q

what is the calculation for Vd

A

plasma water + extracellular + intracellular volumes

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105
Q

why are bound drugs pharmacologically inactive

A
  • unable to reach target site and elicit a biological response
  • by binding to plasma proteins - the drug is effectively trapped
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106
Q

what is the binding capacity of albumin

A
  • binding of a drug to albumin is reversible
  • low capacity - one drug molecular per albumin molecule
  • high capacity - several drug molecules binding to a single albumin molecule
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107
Q

what is the binding affinity of drugs to albumin

A
  • albumin has strongest affinity for anionic and hydrophobic drugs
  • most hydrophilic and neutral drugs do not bind to albumin
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108
Q

what is the competition for binding between drugs

A
  • drugs with high affinity for albumin can compete for available binding sites
  • drugs with high affinity for albumin can be divided into two classes
  • dependent on dose of the drug > or < than the binding capacity of albumin
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109
Q

what are class I drugs

A
  • dose of drug < binding capacity of albumin
  • dose/capacity ratio is low, therefore binding sites in excess of the available drug
  • most drug molecules are bound to albumin and concentration of free drug is low
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110
Q

what are class 2 drugs

A
  • dose of drug > the number of albumin binding sites
  • dose/capacity ratio is high, most albumin molecules contain a bound drug; the concentration of free drug is significant
  • a relatively high proportion of drug exists in free state
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111
Q

what is the clinical importance of drug displacement

A
  • e.g. interaction between tolbutamide (class I drug: 95% protein bound), and sulphonamide antibiotic (class II drug)
  • displacement of class I drug occurs when a class ii drug is administered simultaneously
  • rapid increase in free fraction of tolbutamide in plasma
  • a new equilibrium will be reached
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112
Q

what is the relationship between drug displacement and Vd

A
  • impact of displacement dependent on both Vd and the therapeutic index
  • if Vd is large, then change in free drug concentration is insignificant
  • if Vd is small, the newly displaced drug does not move into the tissue as much
  • increase in plasma drug concentration is more profound when Vd is small
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113
Q

what is the Vd when high MW and/or protein bound drugs

A

trapped in plasma, low Vd

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114
Q

what is the Vd with low MW, hydrophilic drugs

A

Vd = plasma water + interstitial fluid

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115
Q

what is the Vd with low MW, hydrophobic drugs

A

Vd is high

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116
Q

what is xenobiotic metabolism

A

process by which foreign compounds are metabolised in the body to facilitate their elimination

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117
Q

what are the sites of metabolism

A
  • liver - main site of metabolism
  • GI tract
  • kidney
  • skin
  • lungs
  • plasma - hydrolysis
  • brain
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118
Q

what is the liver function

A
  • detoxicification
  • metabolism of carbohydrates, lipids and proteins
  • synthesis of plasma proteins
  • storage of glycogen, vitamins and minerals
  • bile products
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119
Q

what are the cell types of the liver

A
  • hepatocytes
  • cholangiocytes
  • Kupffer cells
  • stellate cells
  • endothelial cells
  • fibroblasts
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120
Q

what is the liver structures

A

liver
liver lobules
lobule

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121
Q

what is in the liver lobule

A
  • hepatocytes
  • central vein - feeds into hepatic vein
  • sinusoid
  • branch of hepatic artery
  • branch of portal vein
  • bile ductile
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122
Q

what is liver regeneration

A
  • damaged liver cells can be replaced by liver regeneration
  • limited process - repeated damage and exhaustion of regeneration leads to fibrosis and cirrhosis
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123
Q

what causes the need for liver regeneration

A

exposure to xenobiotics can stress and damage the liver - more likely to be damaged buy reactive metabolites
- hepatocyte proliferation
- liver stem/progenitor cell

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124
Q

where are microsomal enzymes found

A
  • smooth ER is the major site of drug metabolising enzymes
  • smooth ER are high in abundance in hepatocytes
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125
Q

where are non-microsomal enzymes found

A

cytosol
mitochondria

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126
Q

what reaction are included phase 1 of drug metabolism

A

most mediated by cytochrome P450 enzymes
oxidation and reduction reactions

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127
Q

what reaction are included in phase 2 drug metabolism

A

conjugation reactions

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128
Q

what happens during phase 1 metabolism

A

functionalisation reactions where a functional group is introduced normally producing a more polar excitable molecule

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129
Q

which molecules require phase 2 metabolism before they can be excreted

A

esterases
oxidases
epoxide hydrolyses
dehydrogenases

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130
Q

what is the structure of cytochrome P450

A

haem proteins - 57 Human CYPs
distinct but overlapping substrates

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131
Q

what reactions are cytochrome P450s involved in

A

genetic polymorphism
genotype-phenotype relationship
subject to induction and inhibition
drug-drug interactions

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132
Q

what is included in cytochrome P450 induction and inhibition

A
  • CYP3A4 - responsible for metabolising 50% of drugs
  • wide substrate specificity
  • most abundant in liver and gut
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133
Q

what is an examples of induction of cytochrome P450

A

St johns wort - induction of CYP3A4 and P-gp

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134
Q

what is an example of CYP450 inhibition

A

grapefruit juice - irreversible inhibition of CYP3A4

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135
Q

what happens during phase 2 metabolism

A

conjugation reactions which detoxify compounds and prepare them for excretion

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136
Q

why do some drugs not require phase 1 metabolsism before phase 2

A

when suitable functional groups for conjugation are already present on the molecules

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137
Q

what are the examples of types of drugs that don’t require phase 1 metabolism before phase 2

A

glucuronyl
sulphase
methyl
acetyl

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138
Q

what are the enzymes involved in phase 2 metabolism

A

UDP-glucuronosyltransferases
sulphontransferases
glutathione S-transferases
N-acetyltransferases
methyltransferases
amino acid conjugating enzymes (e.g. glycine and glutamic acid)

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139
Q

what is the relationship between first pass metabolism and bioavailability

A

first pass metabolism in the liver and gut wall reduces the bioavailability of drugs given PO

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140
Q

What are the factors that can affect first pass metabolism

A
  • genetic variations between individuals in the liver and GI
  • variations between individuals in the liver and GI blood flow
  • gut mitochondria
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141
Q

what are the characteristics of prodrugs

A

increase solubility
high first pass metabolism
instability
poor absorption
target drug to specific sites
taste
pain at site of administration
improve PK
reduce toxicity

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142
Q

how are prodrugs administered

A

administered as an inactive form and require metabolism to become active

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143
Q

what are the examples of pro drugs

A

diacetyl-morphine
codeine
cyclophosphamide

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144
Q

what are cytochrome P450 enzymes

A
  • most important family in phase 1 metabolism
  • contain single haem molecule as prosthetic group
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145
Q

where are cytochrome P450 enzymes found

A

endoplasmic reticulum
mitochordria

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146
Q

what is the function of cytochrome P450 enzymes

A

forms complex that shows maximum absorbance at 450nm when reduced and CO added

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147
Q

what is the cytochrome P450 nomenclature

A

use root CYP followed by family, subfamily and form number
sometimes include allelic variants

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148
Q

what are the functions of cytochromes P450

A
  • xenobiotic metabolism
  • steroid, fatty acid and vitamin oxidation
  • steroid biosynthesis
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149
Q

where does xenobiotic metabolism occur

A

occurs in endoplasmic reticulum

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150
Q

where are the cytochromes P450 for steroid biosynthesis found

A

mitochondria

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151
Q

what are the biochemical properties of cytochromes P450

A
  • monomeric proteins of molecular weight 40 000 to 50 000
  • all contain haem as a prosthetic group
  • regions of the protein concerned with haem and oxygen binding tend to be conserved but area important for substrate binding vary more in sequence
  • crystal structures of most human P450s relevant to xenobiotic metabolism not available
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152
Q

what is the cytochrome P450 reaction

A

DH + NADPH + O2 –> DOH + NADP + H2O

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153
Q

What is the function of NADPH in the cytochrome P450 reaction

A
  • NADPH supplies 2 protons and 2 electrons in an electron transfer process
  • interacts with cytochrome P450 enzyme by electrostatic interaction involving carboxyl groups on the reductase and amino groups on the cytochrome P450
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154
Q

what is the name of the protein used for electron transfer

A

flavoprotein containing a prosthetic group flavin adenine dinucleotide and flavin mononucleotide

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155
Q

what is the name of the protein used for mitochrondrial P450s electron transfer

A

adrenodoxin

156
Q

what is induction of cytochrome P450

A
  • induction represents an increase in the amount of mRNA and protein present
  • different inducers have the ability to induce particular isoforms
  • inducers include polycyclic aromatic hydrocarbons and barbiturates
157
Q

what are the effects of cytochrome P450 mediated reactions

A
  • inactivate many drugs and increase their rate of excretion
  • activate P450-mediated reactions
  • produce toxic molecules from certain harmless drugs e.g. paracetamol
  • activate products e.g. cyclophosphamide
158
Q

what is the tissue distribution of cytochrome p450

A
  • found at highest levels in liver
  • detectable but generally at lower levels in kidney, lung, intestine, adrenals and brain
  • some forms are detected mainly in extra hepatic tissue e.g. CYP1A1, some steroid biosynthetic P450s
159
Q

what are the examples of reactions catalysed by P450s

A
  • N-dealkylation e.f. imipramine, diazepam, codeine, erythromycin, morphine, tamoxifen, theophylline
  • O - dealkylation e.g. codeine, indomethacin, dextramethorphan
  • aliphatic hydroxylation e.g. tolbutamide, ibuprofen, pentobarbital, meprobamate, cyclosporine, midazolam
  • aromatic hydroxylation e.g. phenytoin, phenobarbital, propanol, phenylbutazone, ethinyl estradiol
160
Q

what are the cytochrome P450 isoforms

A
  • each is the product of a different gene
  • they tend to show distinct substrate specificities but there is considerable overlap
  • normally essential to know which P450 metabolites a new drug before it is given a license for therapeutic use
161
Q

what is the importance of P450s in drug metabolism

A
  • 70-80% of all drugs subject to metabolism are P450 substrates
    -almost 90% of these are metabolised by CYP3A4, CYP2D6 and CYP2C9
162
Q

what is the content of p450 isoforms in human liver

A

CYP3A
CYP2C
CYP1A2
CYP2E1
CYP2A6
CYP2D6
CYP2B6

163
Q

how do you identify specific P450 isoforms responsible for metabolism of a drug

A
  • correlation analysis using human liver microsome bank
  • inhibition studies e.g. chemical inhibition or antibody inhibition
  • studies using purified or expressed enzymes
164
Q

what is CYP2D6

A
  • position of oxidation is usually 5 to 7 A from the basic nitrogen
  • some of the population lack this enzyme
  • most substrates are either cardiovascular agents, antipsychotics or antidepressants
  • hydroxylation reactions common
  • not inducible
165
Q

what is CYP2C9

A
  • substrates have areas of strong hydrogen bond forming potential or ion pair formations 5 to 10 A from the site of metabolism
  • substrates include a variety of different drug types but especially NSAISd
  • subject to genetic polymorphism - some individuals show low activity due to amino acid substitutions
  • inducible by barbiturates and rifampicin
166
Q

what is CYP3A4

A
  • highly inducible by glucocorticoids, rifampicin and other compounds
  • considerable structural diversity in substrates unlike CYP2D6 ad CYP2C9. binding site can accomodate large molecules and majority of binding seems to involve hydrophobic interactions
  • N-dealkylation reactions particularly common but also see aromatic hydroxylation
  • effects of genetic polymorphism more limited than for many other P450s
167
Q

what are the other P450 isoforms important for drug metabolism

A

CYP2C19
CYP1A2
CYP2E1
CYP2B6
CYP2C8
CYP2A6

168
Q

what are the factors determining metabolism by specific P450 isoforms

A
  • topography of active site of enzyme
  • degree of steric hindrance of access of Fe-O complex to possible sites of metabolism in substrate
  • ease of electron or hydrogen abstraction from various carbon or heterozygous atoms of the substrate
169
Q

what is the role of CYP1A1

A

major role in activation of polycyclic aromatic hydrocarbons. this enzyme is found mainly outside the liver and is induced by some substrates

170
Q

what is the role of cyp2e1

A

contributes to ethanol metabolism - auto induction

171
Q

what is the role of CYP1A2

A

can activate aryl amine compounds to carcinogens and has an important role in caffeine metabolism

172
Q

what are the non P450 reactions involved in phase 1 metabolism

A
  • oxidation reactions e.g. flavin-linked monooxygenases, prostaglandin H-synthase-dependent co-oxidation, amine oxidases, oxidoreductases
  • hydrolysis e.g. esterases, epoxide hydrolases
173
Q

what are flavin linked monooxygenases

A
  • smaller but similar to the cytochrome P450 family
  • requirement for NADPH and oxygen
  • overlap in substrate specificity with certain P450 enzymes but often yield distinct metabolites
174
Q

what are the properties of FMO

A
  • oxidises nucleophilic nitrogen, phosphorus or sulphur centres
  • contain the flavin as prosthetic group
  • located in the endoplasmic reticulum fraction
  • 5 different isoforms
  • most isoforms are thought to be non-inducible, but an exception is FMO5, which is induced by rifampicin in human hepatocytes
175
Q

which FMO species is found in the human liver

A

FMO3

176
Q

which enzymes are associated with peroxidase activity

A
  • prostaglandin H-synthase
  • myeloperoxidase
  • lactoperoxidase
177
Q

what is prostaglandin H-synthase

A
  • involve co-oxidation of arachinodonic acid to a prostaglandin and a xenobiotic to its oxidised metabolites
  • has cyclooxygenase activity
  • has peroxidase activity
  • co-oxidation of xenobiotic to metabolites
178
Q

what is the oxidation reaction of PGHS

A

arachidonic acid –> PGG2

179
Q

what is the reduction reaction of PGHS

A

PGG2 –> PGH2

180
Q

what makes PGHS different to P450/FMO

A

O atom transferred from xenobiotic is not derived directly from o2 and NADPH is not a cofactor
- for examples high doses of paracetamol can be converted to the toxic N-acetylquinoneminie in the kidney

181
Q

what is monoamine oxidase (MAO)

A
  • a mitochondria enzyme which oxidises by a FAD-dependent pathway
  • main role of MAO is in metabolism of neurotransmitters but also oxidises some drugs
182
Q

what is the reaction mechanism of MAO

A
  • RCH2NH2 + FAD –> RCH=NH + FADH2
  • RCH=NH + H2O –> RCHO + NH3
  • RADH2 + O2 –> FAD + H2O2
183
Q

How dos propranolol a MAOA

A

propranolol –> N-desisopropyl propranolol –> aldehyde intermediate –> naphthoxylactic acid

184
Q

what are the enzyme examples of oxidoreductases (dehydrogenases)

A
  • alcohol dehydrogenase
  • aldehyde dehydrogenase
  • carbonyl reductase
  • NAD(P)H quinone oxidoreductase
    they are all cytosolic except aldehyde dehydrogenase
185
Q

what are the reactions of alcohol and aldehyde dehydrogenases

A
  • RCH2OH + NAD+ –> RCHO + NADH + H+
  • RCHO + NAD+ –> RCOOH + NADH + H+
186
Q

what happens during alcohol dehydrogenase

A

normal method of ethanol detoxification
- CYP2E1 uses excess ethanol as a substrate
NAD+ required as a co-factor
coverts alcohols to carbonyls

187
Q

what is an example of alcohol dehydrogenase

A

ethanol –> acetyaldehyde

188
Q

what is the use of carbonyl reductase

A

catalyses the reduction of a wide variety of carbonyl compounds including
- quinones
- prostaglandins
- menadione
- various xenobiotics

189
Q

what is the general reaction form of carbonyl reductase

A

R-CHOH-R’ + NADP+ –> R-CO-R’ + NADPH + H+

190
Q

what happens during quinone oxidoreductase 1

A
  • two electron reductase, catalyses the reduction of a broad range of substrates
  • reduced quinones directly to hydroquinones, without semiquinoane as an intermediate
  • important in detoxification of quinones, quinone-mines and ago compounds
  • scavenges ROS directly
191
Q

where are esterase’s found

A

found in plasma as well as liver and other tissues - cytosolic and microsomal forms

192
Q

what are the different forms of esterase’s

A
  • butryrylcholinesterase - metabolises aspirin
  • carboxylesterases 1 - metabolises cocain and heroin
  • carboxylesterases 2 - metabolises procaine
  • paraoxonase - metabolises aryl esters, oxon form of organophosphorus compounds
193
Q

what are carboxylesterases

A
  • catalyse the hydrolysis of a wide range of chemicals (esters, thiesters and amides)
  • CE1 prefers substrate with a small alcohol group, large acyl group
  • CE2 prefers a large alcohol group, small acyl group
194
Q

what are butrylcholinesterases

A
  • ChE or BChE
  • major contributor to hydrolysis of aspirin to salicylate in plasma
195
Q

what are epoxide hydrolyses

A
  • specialised type of esterase that in the presence of water cleaves epoxides
  • two difference forms-microsomal and cytosolic with difference substrate specificities
  • important role in benzo[a]pyrene activation and metabolism of a few drugs
196
Q

what is paroxonase

A
  • multifunctional enzyme with arylesterases, lactose and paroxonase activities (also hydrolyses other organophosphorus compounds)
  • synthesised mainly in the liver, also found in plasma
  • has a role in degradation of oxidised lipids
197
Q

what is the role of paroxonase in the degradation of oxidised lipids

A

protects LDL and HDL from lipid peroxidation

198
Q

what is the purpose of conjugation reactions

A
  • compounds have greater molecular weight and are more water soluble
  • less able to pass through cell membranes
  • easier to excrete
199
Q

what is glucuronidation

A
  • most common phase 2 reaction
  • carried out by the uridine diphosphate - glucuronosyltransferase
  • UDP-glucuronic acid required as cofactor
  • endogenous compounds such as steroids, vitamins, bile acids and bilirubin also undergo conjugation by UDPGTs
200
Q

What are the properties of UDP-GTs

A
  • founds only in endoplasmic reticulum
  • monomeric proteins of molecular weight 50 to 60 000
  • no prosthetic group
  • highest levels found in liver but also present in kidney, lung, small intestine, skin and adrenal gland
  • larger number of different isoforms
201
Q

what are the effects of glucuronidation

A
  • promotes excretion and results in loss of biological acivity
  • some glucuronides have biological activity - morphine glucuronide
  • some drug glucuronides are reactive and can bind irreversibly to cellular proteins
  • can trigger an immune response
202
Q

what is the difference between UGT1 and UGT2

A

there are different UGT1 isoforms but all products of the same gene whereas UGT2 isoforms are all products of separated genes

203
Q

what is the drug substrate specificity of main UGT isoforms

A
  • UGT1A1 - bilirubin, ethinyl estradiol
  • UGT1A4 - imipramine, amitriptyline, chloropromazine
  • UGT1A6 - paracetamol
  • UGT1A6 - valproate, naproxen
  • UGT2B7 - morphine, ibuprofen
204
Q

how are glucuronidated compounds

A
  • glucuronide conjugates of MW>400 tend to be excreted in the bile whereas those <400 are mainly excreted in urine
  • glucuronides excreted in bile may undergo enterohepatic recirculation, which may potentiate the pharmacological activity of the drug
205
Q

what is the glucuronidation reaction

A

UDP-glucuronic acid reacts with alcohol, carboxylic acids, amines and amides and thiols

206
Q

what is the induction of UDP-GT

A
  • expression of some UDPGT isoforms can be increased by exposure to certain xenobiotics, though induction is modest compared to CYPs
  • family 1 enzymes induced by both phenobarbitone and polycyclic hydrocarbons, but these inducers are not UDP-GT specific
  • more specific inducers operate through the antioxidant response element
207
Q

what are sulphotransference

A
  • soluble cytosolic enzymes with two subunits of MW each approx. 34 000
  • ## wide tissue distribution
208
Q

what are the sulphotransferases important in xenobiotic metabolism

A

SULT1A1 - main liver isoform
- simple phenolic compounds, paracetamol, N-hydroxyl PhIP
SULT1A3 - high in intestins
- simple phenol, 1-hydroxymethylpyrene
SULT1C2, IC4 - fetal liver, kidney, stomach
- simple phenols, N-hydroxy-2-acetylaminofluorene

209
Q

what are the examples of sulphating

A
  • sulphate esters much more soluble - anionic
  • usually pharmacologically inactive
  • can lead to reduced availability of drugs
210
Q

why is sulphating used instead glucuronidation for conjugating reactions

A
  • sulphate tends to be important at low substrate concentrations due to sulphate availability being limited
  • PAPs is an expensive commodity
  • although most drugs are inactivated by sulphation, minoxidil used in the treatment of baldness and hypertension required sulphating for activity
211
Q

how are sulphotransferases regulated

A
  • the metabolites of nuclear aryl hydrocarbons receptor ligands such as dioxins are substrates for SULTS
  • AhR ligands have negative effects on SULT activity in mice, but nor in humans
  • evidence is emerging for a role for orphan nuclear receptors such as constitutive androstane receptor and pregnant X receptor
212
Q

what happens during amino acid conjugation

A
  • requirement for carboxylic acid
  • occurs in mitochondria
  • in humans, glycine, taurine and glutamine are the major conjugating amino acids
  • reaction proceeds by activation of the carboxyl group to its acyl-coenzyme A derivative followed by amide formation with the amino group of the conjugating amino acids
213
Q

what is the reaction during amino acid conjugation

A
  • initial reaction usually carried out by mitochondrial xenobiotic medium chain fatty acid - CoA ligases
  • at least 2 mitochondrial glycine N-acyltransferases occur - one conjugates both benzoic acid and salicylic acid
214
Q

what is acetylation

A
  • acetylation of compounds containing amino, hydroxyl and sulfhydrul groups carried out by acetyltransferases
  • acetyl CoA donates acetyl group
  • NAT1 and NAT2 have been detected in human cytosol
215
Q

why are so few xenobiotics conjugated to amino acids

A
  • believed that many xenobiotics are substrates for MACsd
  • N-acyltransferase is selective; not all CoA thirsters formed by MACs are conjugated
  • salicyl CoA is extensively conjugated
216
Q

what is inactivation of isoniazid by NAT2

A
  • capacity for N-acetylation was the cause of individual variation in metabolism
  • slow acetylation phenotype was recessive trait
  • isoniazid toxicity was associated with slow acetylator phenotypes
217
Q

what are the properties of acetyltransferases

A
  • both the main human NATs isoforms found in cytosol
  • small proteins which are products of adjacent genes
  • NAT1 expressed in most tissues but NAT2 mainly in liver and intestines
  • both enzymes show distinct but overlapping substrate specificities
  • not inducible
218
Q

how does monomorphic and polymorphic acetylation different in NATs

A
  • NAT1 shows some genetic polymorphism but less than NAT2
  • NAT1 is sometimes referred to as the monomorphic NAT
219
Q

what are the examples of NAT drug substrates

A
  • isoniazid (NAT2)
  • sulphamethoxazole (NAT1)
220
Q

what are the effects of acetylation

A
  • results in the masking of amine group with acetyl group decreasing solubility
  • acetylation may activate certain procarcinogens
  • some acetylated compounds can undergo deactivation by a specific esterase enzyme
221
Q

what is the relationship between NATs and cancer

A
  • NATs catalyse inactivation of drugs and aryl amine carcinogens
  • but also activate some heterocyclic and aromatic aryl amines in well cooked food
  • activation by NATs produces reactive intermediated that initiate carcinogens
222
Q

what is glutathione

A
  • tripeptide important in maintaining reduced environment within the cell
223
Q

what is glutathione S-transferase (GST)

A
  • mainly soluble enzymes found in cytosol
  • consist of homo or heterodimers of subunits of Mr approx. 25 000
  • conjugate reduced glutathione to electrophilic compounds through nucleophilic cysteine thiol groups
  • found in most human tissues
  • large number of different isoforms
224
Q

which are the most important forms of GST in drug metabolism

A
  • alpha class (GSTA1-A4)
  • mu class (GSTM1-M5)
  • pi class (GST-P1)
  • theta class (GST-T1, GST-T2)
225
Q

which classes of GST are inducible

A
  • alpha and mu
  • range of inducers include polycyclic aromatic hydrocarbons barbiturates and also antioxidants
  • GST induction thought to be protective against some carcinogens
226
Q

what is the reaction pathway of glutathione conjugation

A
  • glutathione bonds through a nucleophilic cysteine thiol group
  • very reactive with electrophilic substance
  • nucleophilic substitution of acetates, sulphates, nitrate and epoxides
  • conjugates lose glutamic acid and glycine
  • cysteine is N-acetylated to give stable mercapturic acid derivatives
227
Q

which drugs are conjugated by GST

A
  • anti-cancer drug - cyclophosphamide
  • vasodilator - nitroglycerine
  • analgesic - paracetamol
  • diuretic - ethacrynic acid
228
Q

which groups of substrates does methylation act on

A

amine
thiols
alcohols

229
Q

which groups of substrates does acetylation act on

A

amines
amides
hydrazines

230
Q

what are the different methyltransferase families

A
  • O-methyltransferases (catechol and phenol)
  • N-methyltransferases (histamine, nicotinamide)
  • S-methyltransferases (thipurine, thiol)
231
Q

what happens during methyltransferase reactions

A

all methyltransferases use S-adenosylmethionine as co-factor

232
Q

what are the mechanism of induction of xenobiotic metabolising enzymes

A
  • increased levels = induction
  • decreased levels = repression
233
Q

what is the klingenberg experiment

A
  • spectrophotometry - reduced microsomes vs reduced microsomes + CO
  • identified the presence of a haemoprotein
  • Fe3+ - yellow oxidised
  • Fe2+ - red reduced
234
Q

how does induction increase gene expression

A
  • DNA makes RNA makes protein
  • the complement of the negative strand is synthesised to give a copy of the gene
  • pre-mRNA is spliced to mrna
  • translation
  • mRNA is continuously transcribed and translated. it is continuously broken down
235
Q

what is the use of northern blotting

A

measuring the amount of a mRNA

236
Q

what is the use of promoter-reporter expression

A

measuring the amount of transcription

237
Q

what are the approaches for confirming signalling mechanism

A
  • knock out or knock in - known in the human PXR but the mouse PXR is still present
  • knock out and knock in approach - take PXR mice and knock in hPXR
238
Q

what are the nuclear receptors that bind steroid

A

glucocorticoid receptor
mineralocorticoid receptors
androgen receptor
oestrogen receptors

239
Q

what are the nuclear receptors that bind other ligands

A

retinoid X receptor
retinoid acid receptor
thyroid hormone receptor
vitamin D receptors

240
Q

what are the nuclear receptors that bind bile acids

A

pregnant X receptors
constitutive activated receptor

241
Q

what are the specific response elements that bind nuclear receptors

A

two half sites related to
- AGGTCA
- steroid hormone receptor
- bind as homodimers
- imperfect palindromic sequences
- 3bp spacing

242
Q

what are the classes of inducers

A
  • CYP1A - AhR
  • CYP2B - CAR
  • CYP3A - PXR
  • CYP4A - PPARa
  • CYP8A - LXR, FXR
243
Q

what are CYP1A

A

polyaromatic hydrocarbon
tryptophan derived products

244
Q

what are CYP2B

A

phenobarbitone drugs
bile acids

245
Q

what are CYP3A

A

many drugs
bile acids

246
Q

what are CYP4A

A

fibrate drugs
fatty acids

247
Q

what are CYP8A

A

cholesterol
bile acids

248
Q

what are some of the examples of the pharmacological consequences of induction

A
  • rifampicin and contraceptive pill may result in decreased protection against pregnancy
  • barbiturate tolerance
  • enhanced metabolism of certain drugs in smokers and those who eat a lot of barbecued food
249
Q

what are the characteristics of non-specific CYP inhibitors

A
  • often bind haem prosthetic group
  • all active CYPs require haem/O2 for activity
  • B-13 cells have a disrupted CYP1A2 gene
  • no message
  • no protein
  • engineered to express hCYP1A2
  • MROD activity - inhibited by furafylline
250
Q

what are the different CYP450 inhibition

A
  • competitive inhibition by a non-substrate
  • competitive inhibition by another substrate
  • mixed competitive/uncompetitive inhibition
  • irreversible inhibition - suicide substrate
251
Q

what are the clinical examples of CYP3A4 inhibition

A
  • azalea antifungal agent
  • macrolide antibiotic
  • grapefruit juice can result in cardiac arrhythmias
252
Q

what is a clinical example of therapeutic inhibition of CYP metabolism

A

disulphiram
- inhibits aldehyde dehydrogenase
- this causes build up of acetaldehyde if an individual drinks alcohol

253
Q

when can inhibition become a problem

A
  • two drugs are metabolised by the same enzyme
254
Q

how does age effect xenobiotic metabolism

A
  • in the foetus and neonates levels of drug metabolising enzymes are low
  • ion in the foetus and neonate levels of drug metabolising enzymes are low
255
Q

how do CYPs affect xenobiotic metabolism

A
  • the isozyme CYP1A2 is involved in the metabolism of aromatic amines, acetaminophen, imipramine, warfarin, caffeine and theophylline
  • in the metabolism of caffeine and theophylline - CYP1A2 is involved in all demethylations as well as in ring hydroxylation although other isozymes also contribute to these reaction
256
Q

how do differences in species affect xenobiotic metabolism

A
  • animal species can vary in their ability to metabolise xenobiotics
  • coumarin is found in a wide variety of plants, microorganisms and in some animal species
257
Q

why was the use of coumarin banned

A
  • the finding of hepatotoxic effects in rats and dogs fed coumarin in the diet
258
Q

how is coumarin metabolised in humans

A

coumarin –> CYP2A6 –> 7HC

259
Q

how is coumarin metabolised in rats

A

coumarin –> cyp1a/cyp2e –> 3,4 epoxide –> oHPA
3,4 epoxide is toxic and carcinogenic

260
Q

coumarin in flavouring

A
  • it is still present naturally
  • not listed as an authorised flavouring in the EU
  • CYP2A6 polymorphism
  • not an in vivo genotoxin
  • non-genotoxic mechanism - therefore has a threshold
261
Q

what is the reaction of glucuronul transferases

A
  • conjugation of sulphate to glucuronic acid to substrates
  • IDP-glucuronic acid + X-O-H –> (GT) X-G + UDP
262
Q

what is the reaction of sulphotransferases

A

3’ phosphoadenosine-5’phosphosulphate + X-O-H –> (SULT) X-S + PAP

263
Q

how do species difference effect strains

A
  • different strains of rodents may show differences in metabolism usually due to genetic deficiency
  • for example - female DA rats lack rat equivalent of CYP2D6 and is unable to hydroxylate debrisoquine
  • gunn rate - unable to synthesise certain phenol glucuronides
264
Q

how does AhR differ in different mouse strains

A

CYP1A1 - paradigm for the transcriptional regulation of drug metabolising genes

265
Q

what are the hormones affecting P450 levels in rats

A

growth hormones
oestrogen
progesterone
testosterone
insulin
thyroid hormone
glucocorticoids

266
Q

what are the consequence of differences in CYP isoforms

A
  • sex differences due to sex hormones (testosterone and oestrogen) and sex differences in growth hormone secretion
267
Q

which CYP enzymes effect growth and sex in rats

A
  • growth hormones - specific effects on CYP2C enzymes
  • levels increase at puberty and up-regulate expression of CYP2C7, 2C11, 2C12 and 2C22
  • female rats-continuous high levels - induce CYP2C7 and 2C12
  • male rats - intermittent levels
268
Q

what is the effect of increased hepatic expression of CYP2E1 in rat models of diabetes

A

glucocorticoids - synthetics analogues known to induce enzymes of CYOP3A family but natural forms may inhibit drug metabolism

268
Q

what are the effects of liver disease on drug metabolism

A

alcoholic liver disease
cirrhosis
porphyria

269
Q

how does alcohol effect drug metabolism

A
  • may get inhibition of certain drug metabolising enzymes due to changes in NAD(P)H/NAD(P) ratio
  • may get direct inhibition of certain drug metabolising enzymes - CYP2E1
  • competitive metabolism of other drugs e.g. paracetamol
  • induction of certain P450 enzymes resulting in increased metabolism of some drugs
270
Q

what is porphyria

A
  • impaired synthesis of haem and accumulation of toxic precursors
  • levels of cytochrome P450 enzymes may be lower due to limitation in supply of haem
  • drugs such as barbiturates which induce P450s will trigger increased synthesis of haem precursors triggering a clinical attack
271
Q

what are genetic polymorphisms

A
  • can be base substitution, insertion or deletion
    -functional polymorphisms often due to amino acid substitution, splice site change or effect on transcription factor binding
272
Q

how can we analyse phenotyping

A

measure enzyme activity directly by giving a probe drug and measuring metabolites or direct enzyme assay

273
Q

how can we analyse genotyping

A
  • look directly for presence of mutation in individuals DNA
  • need to know gene responsible for the defect and what mutation to scene for
274
Q

what are the characteristics of CYP2D6

A
  • 9 exons
  • metabolism of 1/4 of all drugs
  • highly polymorphic
  • > 100* alleles reported
275
Q

what are the common losses of activity of CYP2D6 polymorphisms

A
  • CYP2D6*3 alleles - A deletion
  • CYP2D6*4 allele - different digestion patterns with restriction enzyme BstNI
  • CYP2D6*5 alleles - entire CYP2D6 gene is deleted
276
Q

how is CYP2D6 an ultra rapid metaboliser

A
  • individuals can have extra copies of the CYP2D6 gene adjacent to the wild type CYP2D6
  • between 2-13copies
  • gene duplication denotes by an xN following the * allele
  • extra genes result in more enzymes and faster drug metabolism
277
Q

what are the consequences of CYP2D6 polymorphism

A
  • failure to metabolise drugs/active metabolites and greater risk of toxicity
  • inability to activate prodrugs
  • poor response to certain antidpresseants due to fast metabolism
  • may suffer toxicity to prodrugs
278
Q

how are CYP2D6 and codeine related

A
  • opiate prodrug
  • metabolism of codeine to morphine dependent on CYP2D6
  • severe respiratory depression in UM children
  • increased morphine breast milk of UM BF mothers
279
Q

what is N-actylation polymorphism

A
  • NAT2 acetylates a variety of xenobiotics including isoniazid
  • individuals with normal activity are fast acetylators
  • slow acetylators have 2 mutated copies of the gene
280
Q

what is the effect of the NAT2 variation isoniazid

A
  • slow acetylators more likely to have increased risk of hepatotoxicity
  • fast acetylators more likely to show poor response to intermittent dosing
281
Q

what is the effect of NAT2 variation hydralazine

A

slow acetylators and autoimmune systemic lupus erythematous

282
Q

what causes toxicity of drugs

A
  • biotransformation is a major cause of toxicity
  • direct biotransformation of parent drug to toxic metabolite
    metabolites which are subsequently metabolised to toxic metabolites
283
Q

what is reaction phenotyping

A

to identify the specific enzymes responsible for the metabolism of a specific drug

284
Q

what are hepatocytes

A
  • parenchymal cells of the liver
  • ability to assess whether compound passes through membrane
  • immediate cryopreservation is import - can still result in loss of enzyme function
  • when cultured over long period loses functionality
285
Q

when are microsomes used

A
  • primarily useful for CYPs and UGTs
  • microsomes can easily be derived from any organ
  • cryopreserved without loss of enzyme function
286
Q

why do activity levels vary in a bank of human liver microsomes

A
  • genetic variation
  • lifestyle differences
  • different personal lifetime exposure to inducers
287
Q

why do we use a human liver microsome bank to study metabolising activity

A
  • can measure various P450s in these microsomes using enzyme assays and immunoblotting
  • with new compounds, measure levels of activity of interest in each microsome preparation
288
Q

why do we use S9 fractions

A
  • the liver S9 fractions contain both cytosolic and microsomal fractions
  • almost same as hepatocytes for phase 1 and phase 2 enzymes
  • s9 fractions are therefore a more representative compared with microsomes and cytosolic fractions
  • presence iof soluble co-factors but may be diluted
289
Q

what is the general requirement for P450 expression

A

need full length cDNA for the isoform of interest available

290
Q

what are the characteristics of transient expression

A
  • disappears over time
  • cDNA in nucleus but does not achieve genomic integration
  • gene not reproduced
  • short period of expression
  • good for short term experiments
291
Q

what are the characteristics of stable expression

A
  • expression maintained through cell lineages
  • genomic integration of cDNA
  • gene inherited through mitosis
  • daughter cells express
  • good for long term experiments/libraries
292
Q

what are the P450 expression systems

A
  • ecoli - requires optimisation
  • yeast - widely used system
293
Q

how does e coli works as a P450 expression system

A
  • cDNA N-terminal sequence modification
  • change residue immediately after initial met to Ala
  • increase AT content of 5’ end
    add his residues at 3’ end
294
Q

what are the outcomes of e coli as a P450 expression system

A
  • amount of active enzyme very variable
  • can remove part of N-terminus making P450 soluble
295
Q

how does yeast work as a P450 expression system

A
  • endogenous p450 oxidoreductase
  • some strains express human oxidoreductase
  • perform more post translational modifications
  • membrane organelles
  • can isolate P450 containing microsomes –> downstream application
  • cheap and scalable
296
Q

what are the issues with P450 expression in E.coli

A
  • no internal membrane system
  • P450s have nothing to anchor into
  • express/purify/reconstitute/investigate
297
Q

what are the issues with P450 expression in yeast

A
  • yeast already express own P450s
  • difficult to isolate/investigate introduced P450 of interest
298
Q

why would you use insect cell P450 expression

A
  • carry out more complex post-translational modification than bacteria or yeast
  • co-transfect P450 and oxidoreductase
  • baculoviral vectors are technically demanding to work with
  • higher cost, longer duration
  • microsome isolation
  • supersedes commercially available
299
Q

what is the expression of non-P450 metabolic enzymes

A
  • sulphotransferases, GSTs and several other families can be readily expressed in e.coli
  • UGT and FMO more difficult but like P450s now expressed in insect cells using baculovirus
300
Q

what are the benefits of studying P450 expression in mammalian cells

A
  • particularly useful for toxicity studies
  • relatively cheap and easily accessible, infinite supply
  • more human relevant and related intracellular environment
  • ensure proper protein folding, post-translational modification and localisation
  • similar control pathways
301
Q

what are COS cells

A

monkey kidney cells that have little endogenous P450 but adequate P450 oxidoreductase

302
Q

why use COS cells for transient expression

A
  • can get P450 expression simply by cloning cDNA into vector with strong promoter and transfecting cells
  • plasmid has SV40 origin of replication, COS cells express SV40 T antigen, plasmid is replicated within the cell
  • transient expression a major limitation for toxicological studies
303
Q

why do we study expression in human lymphoblastoid cells

A
  • G0 –> G1 stimulation = immortalisation
  • transfect with P450 cDNA
  • treat with compound
  • isolate metabolites
  • investigate toxicity and mutagenicity
304
Q

what is chemical inhibition

A

isoform specific inhibitors should be added to the incubation mix of human liver microsomes and drug substrates

305
Q

what are the examples of chemical inhibitor use

A
  • furafyllrin - CYP1A2
  • sulfaphenazole - CYP2C9
  • quinidine - CYP2D6
  • troleandomycin - CYP3A4
306
Q

what is antibody inhibition

A
  • polyclonal or monoclonal antibodies known to affect activity of certain isoforms/raised against specific isoforms
  • pre incubate antibody with human liver microsomes before adding substrates
307
Q

what is high throughput CYP screening

A
  • use of fluorogenic substrates
  • high-throughput
  • less labour intensive vs HPLC/LCMS
  • could give initial idea of which CYPs are involved to study further using marker reactions/probe substrates
308
Q

why used humanised mice

A
  • knock in specific CYPs after knocking out equivalent mouse genes
  • can also transplant human liver/hepatocytes into immunodeficient mice after destruction mouse liver
309
Q

why use hepatic cell lines

A
  • easier to maintain and culture for experiments
  • human hepatoma cell line hEPg2 is the liver cell line most commonly studied
  • metabolic activity of tumour lines is significantly lower than that of primary hepatocytes
310
Q

what are in silicon computational methods used for

A

predict regioselectivity
predict metabolites
predict interactions of drugs with metabolising enzymes
predict toxicological effects of metabolites

311
Q

how can we calculate amount excreted (tubular handling)

A

amount excreted = amount filtered - amount reabsorbed + amount secreted

312
Q

how can we calculate amount filtered

A

when the left untouched by nephron amount excreted = amount filtered (insulin creatine)

313
Q

how can we work out filtered then reabsorbed

A

amount excreted < amount filtered (e.g. glucose, amino acids, Na+)

314
Q

how can we work out filtered and secreted

A

amount excreted > amount filtered (PAH, drug molecules, metabolic end products)

315
Q

what is the urinary excretion of PAH

A

filtered and secreted in tubules
amount in urine always more than amount filtered

316
Q

what is the urinary excretion of insulin

A

filtered amount in urine - proportion to Insulin x filtration rate

317
Q

what is the urinary excretion of glucose

A
  • filtered then reabsorbed - amount in urine less than amount filtered
  • at low concentrations all filtered, glucose reabsorbed
318
Q

what is the calculation for renal excretion

A

total renal clearance = CL by filtration + CL by secretion - retention by reabsorption

319
Q

what is the relationship between drug metabolism and renal excretion

A
  • drugs (active) metabolised mainly to inactive metabolites. renal function does not greatly affect elimination of active compound
  • drug (active) and/or active metabolites excreted in the kidneys
  • change in renal function affect elimination of active compounds
320
Q

what is the mechanism of glomerular filtration

A
  • glomerular capillaries allow molecules with MW < 20 000 to diffuse into filtrate
  • plasma albumin held back
  • drugs enter the filtrate
321
Q

how does protein bind affect filtration

A
  • if drug bound to plasma proteins –> concentration of drug in filtrate = free unbound drug therefore clearance by filtration reduced
  • filtration directly proportional to GFR and the fraction of unbound drug in plasm
322
Q

what is the rate of clearance by filtration

A

fu x GFR
GFR = 120ml/min

323
Q

what is the filtration of creatinine

A
  • creatinine clearance rate is used as a measure of elimination rate
  • creatinine is filtered but neither reabsorbed or secreted so CL=GFR
324
Q

what is the clearance of passive tubular reabsorption

A
  • if CLr < fu x GFR, then renal absorption is taking place
  • Car significantly affected by changes in urine flow rate
325
Q

how are ionisation and passive reabsorption dependent on the pH in relation to pKa of drug

A
  • if the drug is ionised at the pH of tubular fluid, reabsorption will be much lower
  • if the drug is unionised, reabsorption will be higher, as the unionised form of the drug can diffuse through the proximal tubule cell membrane
326
Q

how well can weak acids be reabsorbed

A

weak acids with pKa <7.5 (e.g. aspirin) more highly ionised and less well reabsorbed in alkaline urine
- alkalisation of urine in aspirin overdose reduced tubular reabsorption and increases excretion

327
Q

how well can weak bases be reabsorbed

A

weak bases with pKa > 7.5 (e.g. amphetamine) reabsorption decreases and CLr increases by an acidic urine

328
Q

what is required for active tubular secretion

A
  • if the CLr > fu x GFR, then the drug filtered at the glomerulus is also cleared by active tubular secretion
329
Q

what are the two independent and relatively non-selective carrier systems for active tubular secretion

A
  • acidic drugs and endogenous compounds
  • organic bases
  • carrier systems transport drugs against an electrochemical gradient
330
Q

what are the drugs that causes hyperuricaemia and gout

A
  • diuretic and Low dose aspirin
  • uricosuric drugs - sulphinpyrazone and probenecid
  • allopurinol - first line therapy for gout
331
Q

what are the main determinants for renal drug excretion

A
  • active tubular secretion and passive reabsorption
  • some drugs are not metabolised therefore rate of renal elimination is the main factor in determining duration of drug action
332
Q

what can influence renal clearance of drugs

A

glomerular filtration
reabsorption
secretion in the kidney tubule

333
Q

which drugs can affect dosages due to modified renal function and drug elimination

A

digoxin
ACE inhibitors
aminoglycosides
antibiotics
class 1 anti arrhythmic aagents
cytotoxic agents

334
Q

what is the calculation for creatinine clearance

A

CLcr - rate of urinary excretion of creatine (mg/min)/serum concentration of creatinine (mg/ml)

335
Q

how can CLcr be a measure of GFR

A
  • 1st order renal elimination the relationship is linear
  • e.g. 50% reduction in renal clearance = 50% reduction in elimination of drug
  • drug dosage must be adjusted accordingly
336
Q

what are the implications of renal failure

A

alters passive reabsorption indirectly by alteration in urine flow rate and pH
active tubular secretion is also impaired –> renal clearance of drug affected

337
Q

what is the relationship between renal function and age

A
  • in neonates both GFR and renal tubular function are immature
  • takes ~6months to reach adult levels
  • therefore, drugs and active metabolites excreted by kidneys accumulate in neonates and young infants
338
Q

what is the relationship between renal excretion and old age

A
  • GFR decreases with increasing age (60-70ml/min)
  • tubular function also declines with age
  • reduction in dosage for drugs or active metabolites mainly excreted by kidneys
339
Q

what is the relationship between diet and drug excretion

A
  • renal elimination of certain drugs can be influenced by fasting or starvation
  • e.g. sulfisoxazole (excretion decreases during fasting)
  • drugs eliminated by GFR are affected by nutrition
  • protein loads increase GFR
  • paternal or enteral nutrition may enhance renal elimination of drugs
340
Q

how does pregnancy affect drug excretion

A
  • GFR increases by 70% in pregnancy
  • therefore drugs mainly eliminated by renal excretion will be cleared more quickly
341
Q

how can NSAIDs affect renal functions

A
  • on an acute basis, prostaglandin important for maintenance of renal function
  • acute renal failure may develop
  • fluid and electrolyte retention can all occur
  • may cause hypertension
342
Q

what are the two main other routes of drug excretion

A

biliary excretion
enterohepatic circulation

343
Q

how are drug excreted by biliary excretion

A

drugs transported from liver to bile by transport systems similar to those of renal tubules and involve P-glycoprotein and other transporters
drugs with MW > 300 excreted in bile (especially polar drugs/conjugates)

344
Q

what are the stages of biliary excretion

A
  • some drugs conjugates (particularly glucuronides) concentrated in bile and delivered to intestine
  • drug conjugate hydrolysed
  • free drug
  • drug reabsorbed and the cycle repeated ‘ enterohepatic circulation’
  • can prolong drug actions
345
Q

when is pulmonary elimination required

A
  • main route of elimination and uptake of volatile anaesthetics
  • medico-legal significance - ethanol concentrations in expired air
346
Q

how can saliva be used for drug excretion

A
  • dependent on lipid solubility and pKa, molecular weight
  • useful for therapeutic drug monitoring
  • analgesics - paracetamol, salicylate
  • anticonvulsants - carbamazepine, phenytoin
  • cardiovascular agents - propranolol
347
Q

what are the factors influencing passage of compounds across cell membranes

A
  • lipid solubility affects passive diffusion
  • degree of ionisation with uncharged molecules cross more efficienctly than charged
  • pH difference between cellular compartments can affect transport of foreign compounds
348
Q

what is the role of drug transporters in absorption

A

role in intestine in both facilitating entry of some drugs but also in preventing access by some xenobiotics including drugs

349
Q

what is the role of drug transporters in distribution

A

role in allowing entry in target organs for activity but also liver for metabolism

350
Q

what is the role of drug transporters in excretion

A

role in both renal and biliary excretion

351
Q

what are the main drug transporter proteins

A
  • ABC proteins (ATP dependent) e.g. MRP family, MDR, BSEP, BCRP
352
Q

What are the names of the SLC family drug transporters

A

OAT - anion transporter
OATP - anion transporter
OCT - cation transporter
MATE - cation transporter
PEPT - mostly peptides but also penicillins

353
Q

what are SLCs

A

solute carrier
52 different gene families that all code for membrane proteins but these proteins have a variety of functions including roles in normal physiology

354
Q

what are the two general types of SLC proteins

A
  • facilitative transporters - allow substrates to flow downhill with their electrochemical gradients
  • secondary active transporters - substrates can flow uphill against their electrochemical gradients by coupling transport to that of a co-substrtate
355
Q

what are the properties of the OATP family

A
  • organic anion-transporting polypeptide
  • families 1 and 2 are the most important in relation to drug disposition
  • important in drugs transport across sinusoidal membrane in liver
  • OAT1B1, OATP1B3, OATP2B1 most important in liver
  • kideny also has OATPs present but more limited role in renal excretion
356
Q

what are the properties of the OAT protein

A
  • members of SLC22A subfamily
  • key role in renal excretion but also expressed elsewhere
  • OAT1, OAT2 OAT3 found on basolateral membrane of proximal tubule cells facing blood vessels
  • OAT4 on apical membrane of proximal tubules, facing urine
357
Q

what is anionic drug transport in renal proximal tubules

A

OAT1/2/3 are coupled to dicarboxylic acid transport
- OAT4 reabsorbed drugs from urine and may be bidirectional

358
Q

what are OAT substrates

A
  • likely to be sulphate or glucuronide conjugates
  • OAT1 - tetracyclines
  • OAT2 - AZT, diclofenace, diclofenac glucuronide
    -OAT3 - oestrone sulphate, benzylpenicillin, rosuvastatin
359
Q

what are OCTs

A
  • organic cation transporters
  • members of SLC22A so some sequence homology of OATs
  • OCT1/2 are the most important cationic transporters in human drug disposition
360
Q

what are OCT1

A
  • important transporter on sinusoidal face of liver though found elsewhere in the body also
  • substrates include metformin and cisplatin
361
Q

what are OCT2

A
  • high levels on basolateral membrane of kidney
  • substrates include metformin and cisplatin also cimetidine
362
Q

what are PEPT transporters

A
  • peptide transporters encoded by SLC15a subfamily
  • both show similar substrate specificities with penicillins, ACE inhibitors and valacyclovir
  • proton-dependent transporters
  • in kidney PEPT1/2 contribute to drug reabsorption from urine within proximal tubules
363
Q

where is pept1 expressed

A

intestine and kidney

364
Q

where is pept2 expressed

A

mainly in kidney

365
Q

what are MATE transporters

A
  • multidrug and toxin extrusion family
  • members of SLC47 family
  • export pumps which contribute to biliary and renal excretion of cations
  • transport is proton dependent
366
Q

where is MATE1 expressed

A

liver and kidney

367
Q

where is MATE2-K expressed

A

kidney only

368
Q

what are the transporter proteins in the intestines

A
  • ASBT - Na dependent bile salt transporter
  • OST - organic solute transporter
  • MCT1 - monocarboxylate transporter
369
Q

what is the role of transporter proteins in the intestines

A

compounds need to enter enterocytes through brush border membrane and then cross basolateral membrane into hepatic portal vein

370
Q

what is the role of transporter proteins in the liver

A
  • xenobiotic often need to be transported into hepatocytes across sinusoidal membrane for both metabolism and to reach targets
  • compounds usually following metabolism need to be transported out either across canalicular membrane or sinusoidal membrane
371
Q

what is the importance of the basolateral membrane in kidney tubules

A
  • compounds excreted by tubular secretion need to enter
  • those being reabsorbed need to return to circulation
372
Q

what is the importance of the brush border membrane in kidney tubules

A
  • compounds need to cross this membrane to enter lumen for final renal excretion
  • reabsorption may occur
373
Q

what is the role of diclofenac excretion in liver and kidney

A
  • diclofenac undergoes metabolism by CYP2C9 and UGT2B7
  • UGT2B7 produces acylglucuronide (DF-AG)
  • OAT2 and OAT4 important in renal excretion of DF-AG
374
Q

Which drug interactions can inhibit OAT transport

A

penicillin and probenecid

375
Q

which drug interactions can inhibit ABCB1 transports

A

digoxin and erythromycin or statins

376
Q

which transporters are inducible by PXR

A

abcb1
abcc2
slco1b1

377
Q

which drugs can interact causing induction via PXR

A

rifampicin, cyclosporin, digoxin

378
Q

what are the pharmacogenetics of OATP1B1

A
  • genetic polymorphism associated with higher plasma levels of some statins due to impaired ability to enter hepatocytes
  • higher plasma levels may lead to toxic levels of statin in muscle cells
379
Q

what are the pharmacogenetics of OCT2

A
  • linked to nephrotoxicity with anti-cancer drug cisplatin
  • may also involve MATE2
  • drug accumulated in tubule
380
Q
A
380
Q

what is the renal handling of cisplatin

A

-

381
Q
A
382
Q
A
383
Q
A

CM2001 (13 decks)

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