4+5: Pharmacokinetics and Drug Metabolism Flashcards
Summarise the journey of a drug through the body (AADME)
Administration
Absorption
Distribution
Excretion
Types of routes of administration
Local - restricted to one area
Systemic - entire organism exposed to drug
Enteral - via GI tract (oral/liquid), easiest
Parenteral - avoiding GI tract (IV)
Pros of IV drug infusion
V quick onset of action - Rapid systemic exposure
High bioavailability
May be used for drugs w short half lives
Route of drug absorption
Drug enters GI tract, absorbed and taken to liver via hepatic portal sysstem and enters systemic circulation.
How would you administer drug if need slow absorption
Intramuscular/dermal routes
How do drug molecules move in the body
- Bulk flow transfer in blood stream
2. Diffusion transfer over short distances
Method of crossing barriers
- Diffusing through lipid (if of a suitable nature)
- Diffusing through aq pore in the lipid (if they are polar)
- Carrier molecules
- Pinocytosis- the cell engulfs the molecule and takes it in.
Drug is in dynamic equilibrium w ionised/unionised forms. Ratio of ionised:unionised depends on:
pH of env
pKa of molecules
How does ion-trapping work
When in circulation, drug is in dynamic equibilirium. The unionised form is taken up by proteins whihc traps it in protein-drug complex. This prolongs half life of the durg
Factors influencing distribution of drug
Regional blood flow
Extracellular binding (plasma-protein binding)
Capillary permeability
Localisation in tissues
Describe how regional blood flow effects distribution of the drug
o Tissues w high perfusion are likely to be exposed to a higher concentration of the drug.
o Some tissues may increase in perfusion when their activity increases e.g. skeletal muscle
o Highly metabolically active tissues tend to have a greater blood flow and denser network of capillaries so absorb quicker
Describe how extracellular binding (plasma protein binding) affects distribution of the drug
When drug is bound to a plasma protein, it cant be absorbed. It will persist for long time whilst bound.
50-80% of acidic drugs tend to bind plasma proteins
Desccribe how capillary permeability affects distribution of drugs
Diff tissues have diff permeabilities. Distribution depends on capillary structure:
Fenestrated= more permeable to drugs
Continuous= found in normal vessels, has water filled gap junctions.
Discontinuous= large gaps between endothelial cells
Describe how localisation in tissues affects drug distribution
Fat isnt highly perfused so it’s v lipophilic env. Drugs that are lipophylic tend to localise and persist in fatty tissue.
How does liver excrete drugs
Tends to be large molecular weight drugs w tend to b lipophilic concentrated in bile
Abx also tend to be biliary drugs
Biliary excretion can cause problems because of the enterohepatic circulation. The drug or metabolite gets excreted into the gut but then it can get reabsorbed and returned to the liver via the enterohepatic circulation. This leads to drug persistence- increases the duration the drug is left in the body prolong the pharmacology.
How does kidney excrete drugs
Majority of excreted drug gets into urine via active secretion rather than ultrafiltration.
- Glomerulus: drug protein complexes not filtered
- PCT: active secretion of acids + bases
PCT + DCT: lipid soluble drugs are reabsorbed
Other less common routes of excretion of drugs:
lungs breathe air out, sweat, saliva, skin, GI secretions, milk, genital secretions
Define bioavailability
proportion of the administered drug that is available within the body to exert its pharmacological effect.
Define apparent volume of distribution
the volume in which a drug appears to be distributed- an indicator of the pattern of distribution.
Define biological half life
the time taken for the concentration of a drug (in blood/plasma) to fall to half its original value.
Define clearance
vol of plasma cleared of the drug per unit time
Define first order kinetics
First Order Kinetics: amount of drug decreases at a rate which is proportional to the concentration of drug remaining in the body.
Clearance of drug following first order kinetics can be mathematically shown as:
Cl = Vd x Kel (where Kel = Log2/t0.5)
Define zero order kinetics
A constant amount of drug is removed per unit time, amount of drug decreases at a rate independent of the concentration of a drug remaining in the body.
What does 0 order kinetics imply
It implies a saturable metabolic process, usually enzymic. Once the enzymes are saturated, the rate of removal of the drug peaks and remains constant.
Clearance of drug following 0 order kinetics can be mathematically shown as:
Cl (clearance of drug) = time x Kel (where Kel = dC/dt)
Give an example of something that follows zero order kinetics
alcohol
Define hepatic first pass metabolism
metabolic conversion of the drug into something that’s diff before the drug enters general circulation/ effect that occurs the v first time that drug passes through liver
What happens in Phase 1 metabolic change
Polarity remains largely unchanged.
3 types of Phase I chemical activtiy includes: oxidation, reduction + hydrolysis
Functional groups serve as point of attachment for phase 2 reactions
It often inactivates chemicals but can also activate them (prodrugs).
What happens in Phase 2 metabolic change
GGAASM
Addition of large polar endogenous groups to drugs to allow excretion as more water soluble. 6 types of chemical acctivity:
Glucorodination Glutathione conjugation Acetylation Amino acid conjugation Sulphation Methylation
How many enzymes involved in cytochrome P450 system and where are they found
57
liver + SER
Cytochrome P450 mediated oxidation reaction
RH (drug) + NADPH + O2 + H+ = ROH (oxidised drug) + NADP+ + H2O
Cyclic manner of CYP450 enzyme and its oxidation reactions (8steps)
- Drug binds to P450 at catalytic active site and interacts w Fe3+ w is in oxidised state.
- Electron is donated by NADPH (it’s preferred over NADH); it’s picked up by P450 complex, reducing Fe3+ to Fe2+.
- Molecular O2 binds to catalytic active site.
- Electron rearrangement occurs. Fe2+ loses e (Fe3+) and O2 carries the extra e and becomes unstable.
- A second e from NADPH reduces Fe3+Fe2+.
- Fe2+ donates e to O2 (Fe3+). O2 is v unstable. Drug is still unchanged
- Drug is converted to hydroxylated derivative. Cleave the reactive oxygen as water by picking up two protons.
- Drug is released and P450 returns to the cycle with iron in oxidised state (Fe3+) ready to undergo the next cycle
4 oxidative reactions
- Hydroxylation
- N-demethylation: oxidation of methyl group in N env (C on an N)
- O-demethylation: oxidation of methyl group on an O
- N-oxidation: oxidation of N group. This generates an amine oxide. Flaving containing monooxygenase catalyses this reaction.
- Alcohol oxidation: alcohol dehydrogenase catalyses it. has 0 order kinetics. Alcohol is metabolised into acetaldehyde and then to acetic acid.
Flavin Containing Monooxygenase Deficinecy
Humans generate trimethylamine in their GI trac w smells terrible + is lipophilic.
Liver: FCM converts trimethylamine into trimethylamine N-oxide w is odourless + polar so cna be excreted in urine.
Those w FCM deficiency produce trimethylamine but cant metabolise + excrete it so sweat/breathe it out aka fish odour syndrome.
Which order reactions are P450 + flavin containg monooxygenase
first-order reactions
Reductive reactions are less common. Where do they take place
GIT as low O2 env. Most reductases are bacterial enzymes colonising our gut.
Hydrolysis enzymes
Esterase: hydrolysis of ester
Amidase: hydrolysis of amide
Enzymes for each Phase 2 reaction
Glucorodination: glucuronyl transferase Gluthione: glutathione-S-transferase Acetylation: acetyl transferase Amino acid conjugation: acyl transferase Sulphation: sulphotransferase Methylation: methyl transferase
Conjugating agent + target functional group for glucuronidation
UDP-glucuronic acid
-OG, - COOH, -NH2, -SH
Conjugating agent + target functional group for glutathione conjugation
glutathione
electrophiles
Conjugating agent + target functional group for acetylation
Acetyl Co A
-OH, NH2
Conjugating agent + target functional group amino acid conjugation
glycine, glutamine, taurine
-COOH
Conjugating agent + target functional group for sulphation
3’-phosphoadenosine-5’-phosphosylphate
-OH, -NH2
Conjugating agent + target functional group for methylation
S-adenosyl-methionine
-OH, -NH2
Most common phase 2 reaction
glucuronidation
Glucoronidation
Catalysed by glucuronyl transferase to form the sugar derivative of the xenobiotic.
It makes quite a large molecular weighted molecule so has issues w glomerular filtration and is often excreted by bile
Methylation’s effects on polarity
it decreases it
Sulphation
xenobiotic is taken w PAPS w is a sulfate donor. It is sulfated to produce sulfuric acid derivative of molecule which is v polar + Water soluble
Which phase 2 reaction is imp process toxilogicallyh
glutathione conjugation - glutathione is tripeptide (glycine, glutamine + cystein). It reacts w electrophiles w must be removed bc damage DNA + proteins
Imp part of glutathione molecule is
cystein bc it has thiol which is the part which reacts w electrophiles
