Drug Disposition Flashcards
Galetin teaching
Define pharmacokinetics.
How the body responds to drugs
Define pharmacodynamics.
The impacts the drug has on the body.
What is the main aim of metabolism?
To make the molecule more hydrophilic in preparation for elimination.
Define bioavailability.
A measure of the extent of absorption of unchanged administered compound.
What is distribution?
Reversible transfer of a substance between site of administration and site of measurement.
What is metabolism?
Irreversible loss of unchanged substance by chemical conversion.
What is elimination?
Irreversible loss of unchanged substance from site of measurement.
Name 6 factors that influence pharmacokinetics?
Genetics Age Size of molecule Disease state Concomitant drugs Environment
What are the names of two pharmacokinetic models?
Single equation, integrated
Kinetic compartmental
Define rate of change in an equation.
Rate of change = rate of absorption - (rate of excretion + rate of metabolism)
What is the main reason that the effectiveness of a drug molecule will eventually plateau?
Receptor saturation
Name 6 physiological parameters affecting drug action.
Tissue volume Blood flow Tissue composition Intestinal pH Gut transit time Enzyme/transporter abundance
What is absolute bioavailability?
Bioavailability assessed with reference to an IV dose
What is relative bioavailability?
Comparison of different formulations of the same drug
Define bioequivalence.
Formulations containing the same dose intended to be interchangeable.
What impact does a fasted state have on delivery in the GIT?
Rapid delivery to the upper small intestine
What impact does a fed state have on delivery in the GIT?
Can delay gastric emptying by up to 10 hours
When should enteric coating be given? Why?
Given on a fasted stomach to ensure it reaches the small intestine as quickly as possible.
What impact does gastric bypass surgery have on absorption?
Reduces surface area of the stomach and bypasses approximately 75cm on the intestine, main area of drug absorption.
What impact does coeliac disease have on drug delivery?
Expression of intestinal CYP3A reduced to 15%.
What impact does chronic kidney disease have on drug delivery?
Increased gastric pH and emptying time
Can alter CYP450 expressio
What is transcellular movement?
Passive diffusion often via facilitated transport
Continues until equilibrium reached
Increased molecule size reduces permeability
What is paracellular movement?
Transport between epithelial cells mainly via passive diffusion
Important for polar, hydrophilic drugs
What is P-glycoprotein?
Efflux transporter found on the apical membrane of enterocytes and biliary canicular membrane of hepatocytes
Active efflux of drugs into intestinal lumen
What is first pass metabolism?
Metabolism of molecules before reaching systemic circulation. Can occur in the intestine, liver or kidney
F= FaFgFh
What are the pharmacokinetic parameters affecting IM/SC absorption?
Muscle capillary membrane is more porous than the gut, allowing paracellular absorption
Perfusion rate is limited by blood flow
What are the pharmacokinetic parameters affecting transdermal absorption?
Permeability rate is limited, even for lipophilic drugs
What are the pharmacokinetic parameters affecting pulmonary absorption?
Rapid access too systemic circulation due to surface area
Only 2-10% of aerosol actually deposits in the lungs
Name two drugs affecting absorption of paracetamol. Explain why.
Metoclopramide- increases gastric emptying therefore paracetamol reaches SI faster, increasing Cmax and reducing Tmax
Anticholinergics- reduce Cmax of paracetamol and increase Tmax however the AUC remains the same
When does perfusion limited distribution occur?
When the tissue/cell membrane does not represent a barrier to drug distribution
Give 4 examples of highly perfused tissues.
Brain
Lungs
Liver
Kidney
Which tissue do lipophilic drugs have particularly high affinity for?
Adipose
When is permeability limited distribution most likely to occur?
Polar molecules
Relatively impermeable membranes
What are the features of the blood brain barrier relevant for molecule distribution?
Very small pores
Barrier at capillary level
What are the features of the muscle/kidney cells relevant for molecule distribution?
Capillaries porous to small molecules
Barrier at cellular level
What are the 3 key water volumes within the body?
Plasma water 3L
Extracellular water 12L
Total body water 40L
At equilibrium what is the amount of drug in the body defined by?
A= V x C
Where V= volume of distribution and C= concentration
What do acidic drugs show strong affinity to? Give an example.
Plasma proteins
I.e. warfarin
What do basic drugs show strong affinity to? How does this impact the volume of distribution? Give an example.
Acidic phospholipids in tissues, thus have a higher volume of distribution.
I.e. fluoxetine
How do lysosomes affect volume of distribution? Give examples of drugs affected by this.
Sequester cationic amphiphilic drugs
Molecule (logP >2, pH 6.5-11) can accumulate and not reach receptor target
Reduces activity and off target effects of drugs.
I.e. azithromycin, vinblastine
Name the three plasma proteins largely responsible for drug binding. What drugs are likely to bind?
Albumin- acidic and neutral drugs such as cyclosporine
Alpha-1 acid glycoprotein- basic drugs
Globulins- steroids
What is Fu?
Fraction unbound
Fu= Cu/C
What circumstances may alter fraction of drug unbound?
Pregnancy
Liver cirrhosis
Renal impairment
What is Kp?
Tissue to plasma partition coefficient
VpC= KpVtCt
What are the most common drug-drug interactions?
Metabolic DDIs, inhibition or induction of CYP enzymes
Describe the effects of an inhibition DDI.
Reduced metabolising rate, increased drug concentration potentiating drug effect.
Describe the effects of an induction DDI.
Increased metabolising rate, decreased drug concentration and drug effect.
What is Ki?
The inhibitor-enzyme dissociation constant, analogous to Km
What are the 3 classifications of CYP inhibition?
Strong 5 fold increase in AUC
Moderate 2-5 fold increase
Weak 1.25-2 fold increase
AUC ratio= AUC(inh)/AUC
What impact does grapefruit have on drug metabolism?
Irreversible inhibition of intestinal CYP3A4 by furanocoumarins
No effect seen when given IV so minimal effects on hepatic CYP
What is auto-induction? Give a drug example.
A drug increases its own metabolism at an enzyme
I.e. Carbamazepine
What is the common mechanism of enzyme induction?
Requires complement of cellular processes
Increased transcription and translation, reduced degradation
What occurs physiologically upon enzyme induction?
Increased Vmax
Altered Km at enzyme level
Increased CYP synthesis
Pronounced proliferation of endoplasmic reticulum
Increased liver size, weight and blood and bile flow
Describe the clinical consequences of concomitant administration of ketoconazole and terfenadine.
Ketoconazole is a CYP3A4 inhibitor
Terfenadine must be broken down to fexofenadine for action but CYP3A4
Increased levels of terfenadine can cause QT prolongation and severe arrhythmia
What are the two major subfamilies of transporters?
ATP-binding cassette
Solute carriers
Where are the most clinically relevant transporters expressed?
Epithelia of intestine, liver and kidney
Endothelium of BBB
What is OATP?
Organic anion transporting peptide
Located on sinusoidal membrane of hepatocytes
Mediates uptake of drugs and endogenous compounds
Describe the clinical consequences of concomitant administration of cyclosporine and rosuvastatin.
Cyclosporine inhibits OATP1B1
Rosuvastatin is transported into the liver for metabolism via OATP1B1
Inhibition of this increases Cmax and AUC of rosuvastatin leading to rhabdomyolysis
Which drug is responsible for the most relevant P-gp DDIs?
Digoxin
What is the role of BCRP in drug uptake?
Attenuates intestinal absorption of poorly permeable drugs and contributes to biliary elimination
What drug does turmeric most commonly interact with?
Inhibits intestinal efflux of sulphasalazine.
What effect does apple juice have on drug absorption?
Inhibits intestinal uptake of aliskiren and fexofenadine via OPAT2B1
Define renal clearance.
CLr= rate of urinary excretion/concentration in plasma
What percentage of cardiac output do kidneys receive?
20%
What is the average urine flow rate and GFR?
Urine flow= 1-2mL/min
GFR= 120mL/min
What is the rate of renal excretion?
Rate of excretion= (rate of filtration + rate of secretion) x (1-fraction resorbed)
What is active tubular secretion?
Active uptake of compounds via OAT/OCT paired with efflux transporters
Give 4 examples of OAT1 substrates.
Adefovir, oseltamivir, methotrexate, penicillin G
Give 2 examples of OCT2 substrates.
Metformin, pindolol
What two major factors affect reabsorption in kidneys?
Lipophilicity and ionisation
How does urine pH affect renal clearance?
Ranges from 4.5-7.6
Weak acids- CLr is urine pH sensitive, pKa 3-7.5 drug is non-ionised and lipophilic
Strong acids- pKa<3 mostly ionised thus minimal absorption
Weak bases- CLr is urine pH sensitive at pKa 6-12, drug is non-ionised
How does urine flow affect renal clearance?
Flow dependent on CLr occurs when drug is resorbed
If equilibrium is achieved, higher urine volume means higher CLr
What occurs when renal resorption rate = secretion rate?
CLr = fu x GFR
Which CYP enzymes are present in the kidneys?
CYP3A5 in cortex and medulla
CYP2D6 in PT and loop of Henle
Where are carboxylesterases present in the kidneys?
PT and bowman’s capsule
What affect does CKD have on metabolism and elimination?
Reduced CLr and GFR Reduced kidney weight Reduced tubular secretion and transporter expression Reduced CLh Increased gastric emptying time and pH Downregulation of CYP enzymes
What is clearance?
CL= rate of elimination/concentration in plasma
Remains constant irrespective of dose if drug PK is linear
What are the two major sites of metabolism?
Liver and intestine
What is the elimination rate constant (k)?
The fractional rate of drug loss
k= Cl/V
What is flow rate (Q)?
CL= Q(Ca-Cv)/Ca
What is Fh?
Fraction escaping hepatic metabolism
Fh= 1-Eh
What are the three classes of hepatic extraction? Give examples.
Low extraction (<0.3) diazepam, warfarin, phenytoin Medium extraction (0.3-0.7) quinidine, codeine, cyclosporine High extraction (>0.7) propranolol, verapamil, lidocaine
What is the typically blood flow through the liver?
1300-1500mL/min
What is the additivity of clearance?
The total clearance is the addition of the individual organ CL values.
What is unique about the hepatic blood supply?
It has a dual supply: Portal vein (1.1L/min) Hepatic artery (0.4L/min)
What can affect the hepatic flow rate?
Increase- bed rest, thyrotoxicosis, isoprenaline
Decrease- exercise, heart failure, propranolol
What can affect plasma protein binding?
Increase- burns, neonate, nephrosis, heart failure
Decrease- stress, cancer, arthritis, crohn’s, myalgia
What physiological effects does liver cirrhosis have?
Decreased liver volume Portal hypertension Renal impairment CLh reduced Impaired albumin synthesis and protein binding
What parameters are affected by hepatic extraction?
Hepatic clearance only affects drugs with high Eh
Plasma protein binding is important for low Eh drugs
What are the structural requirements for biliary excreted molecules?
Active facilitated transport
Polar
MW >350 Da
What is the average bile flow?
0.5-0.8mL/min
What is bile clearance?
CLb = (bile flow x drug concentration)/drug concentration in plasma
Describe enterohepatic recirculation. Give examples of drugs.
Liver-> common bile duct-> small intestine-> superior mesenteric vein-> portal vein-> liver
Occurs with bile salts, rosuvastatin, mycophenolic acid
Briefly describe how CYP enzymes are classified.
12 families total, 1-4 important in drug metabolism
>60% homology in subfamilies
Which letter/number denotes the family, subfamily and gene?
CYP2D6
Family- 2
Subfamily- D
Gene- 6
Describe the activity of CYP enzymes in disease.
Reduced activity of CYP2D6 and CYP3A4 in cancer and HIV
Downregulation of CYPs mediated by pro-inflammatory mediators
What are the major roles of CYP450?
Membrane bound haem containing proteins
Activation of oxidation and oxidation of drug
What are the binding properties of CYP450 enzymes?
Substrate binding at protein active site
Haem ligand for oxygen and CO binding
CO binding has absorption spectrum max at 450nm
Describe the 6 stages of the CYP cycle?
1- substrate binds to active site, enzyme conformation changes
2- transfer of electron (NADPH-> NADP+) via flavoprotein-1
3- binding of oxygen to harm
4- transfer of second electron, reducing dioxygen to negatively charged peroxy group (NADPH-> NADP+)
5- peroxy group protonated twice forming highly reactive Fe
6- substrate reacts with Fe species, releases hydroxylated product, water molecule returns to distal haem position
Describe the preference for substrates of CYP2D6? Give an example.
Arylalkylamines (basic) with a site of oxidation 5-7 atoms from protonated nitrogen.
i.e. ecstasy
Describe the preference for substrates of CYP2C9? Give an example.
Neutral or acidic molecules with oxidation site 5-8A from H-bond donor heteroatom
Generally amphipathic with lipophilic region at site of hydroxylation
Hydrophilic area around H-bond forming region
i.e. tolbutamide
Describe the preference for substrates of CYP3A4? Give an example.
Neutral or basic molecules
Lipophilic and bulky
Site of oxidation often basic nitrogen
i.e. testosterone or midazolam
Describe the multimodal distribution of CYP2D6.
7% of caucasians are poor metabolisers, lacking CYP2D6 gene
2% of Swedish, 10% of Spanish and 8% of Italians are ultra-metabolisers, have gene duplication
What is the role of phase I metabolism?
Expose functional groups via oxidation at C, N or S atom
What is phase 1 hydroxylation?
Aromatic oxidation to form phenols i.e. lignocaine
Aliphatic oxidation to form alcohols i.e. pentobarbitone or tolbutamide
What is phase 1 cleavage?
O-dealkylation to form phenols i.e. codeine
N-dealkylation to form amines i.e. theophylline
What is phase 1 reduction?
Nitro-reduction i.e. chloramphenicol, nitrazepam
Azo-reduction i.e. prontosil
What is phase 1 hydrolysis?
Catalysed by carboxylesterases
Ester hydrolysis i.e. oseltamivir
Amine hydrolysis i.e. procainamide
What is phase II metabolism?
Conjugation of phase I metabolites for renal and biliary excretion via efflux transporters
What is glucuronidation?
Occurs via UDO-glucuronosyltransferases on luminal side of the endoplasmic reticulum
Glycoproteins (UGT) catalyse addition of glucuronic acid
What are the two key paediatric clinical differences in glucuronidation?
Morphine glucuronidation (UGT2B1) is deficient in young adults UGT1A1 reaches adult levels at 3-6 months, congenital jaundice due increased bilirubin
What is Gilbert’s syndrome?
Unconjugated hyperbilirubinaemia in adults due to deficiency of UGT1A1
What are the three most abundant glucuronidation enzymes in healthy kidneys and tumour tissues?
UGT1A9
UGT2B7
UGT1A6
How does CKD affect glucuronidation?
Inhibition of UGT enzymes by uremic toxins
What is phase II sulphation?
Occurs mainly via cytosolic enzymes, activated by ATP cofactor PAPs
SULT enzymes present in liver and small intestine
Metabolism of drugs such as paracetamol and salbutamol
What is glycine conjugation?
Phase II reaction limited to acids
Drug becomes activated as acyl coenzyme A intermediate
What is acetylation?
Phase II reaction limited to amines
Formation of N-acetyl conjugates via acetyl CoA
What is phase III metabolism?
Prolongs drug effect via action of glucuronidase of sulphates enzymes reversing phase II metabolism
Describe the 3 major metabolites of diazepam.
Temazepam and oxazepam are rapidly metabolised and barely detectable in the plasma but marketed as short acting
Nordazepam has a longer half life and can cause local toxicity at site of formation i.e. liver injury
What is benzopyrene?
A major polycyclic aromatic hydrocarbon in cigarette smoke
Forms a reactive metabolite in the lung causing irritation
What is glutathione conjugation?
Protective mechanism
Electrophilic phase I metabolic interacts with nucleophilic glutathione tripeptide
What occurs in paracetamol overdose?
Electrophilic metabolite forms (NAPQI) which leads to liver cell death
N-acetylcystiene is a well tolerated nucleophile that can be given as an antidote.
What is a type A adverse drug reaction?
Reversible reaction that is dose related
Causes 80% of ADRs
What is a type B adverse drug reaction?
Irreversible, idiosyncratic ADR with a genetic basis, often associated with the liver
What is a type C adverse drug reaction?
Irreversible chemical reaction with tissue macromolecule often leading to necrosis
What is a type D adverse drug reaction?
Irreversible ADR that is chronic, response is often delayed
Under what circumstances, according to the FDA, should a drug metabolite be evaluated as an enzyme inhibitor?
Less polar and present at >25% of parent systemic exposure
More polar and present at >100%
