PH1125 - Drug metabolism Flashcards
Why is drug metabolism important?
recognises potential toxicities, optimisation of prodrugs and prediction of half life.
What are CYP monooxygenases?
Major catalyst of endogenous compounds oxidised in the liver, lungs, kidneys and GI.
what is a pro-drug?
- a biologically inactive compound that can be metabolized in the body to produce a drug
what is absorption?
- transfer of drug from the site of administration to blood
what is distribution?
- (reversible) transfer of drug from one PK compartment to another
what is metabolism?
- chemical conversion of compounds (biotransformation)
what is excretion?
- removal of drug from the body without chemical alteration
what is elimination?
- metabolism and excretion
why are CYP 450 enzymes called that?
- carbon monoxide binds to the reduced Fe(II) haem and absorbs at 450nm
where are CYPs found?
- they are in smooth endoplasmic reticulum (SER) in close association with NADPH-CYP reductase
What are CYP reactions essential for?
production of many things like steroids eg. cholesterol.
How do CYP enzymes work?
catalyse oxidation reactions by changing C-H to C=O group. By radical intermediates.
what does the reductase do in oxidative reactions?
- serves as the electron source
what is an example of CYP mediated biotransformations where there is a formation of an active metabolite?
- codeine to morphine
what is an example of CYP mediated biotransformations where there is a formation of an inactive metabolite?
phenobarbital to hydroxyphenobarbital
what is an example of CYP mediated biotransformations where there is a formation of a toxic metabolite?
- paracetamol to NAPQI
what processes does paracetamol undergo to form NAPQI? (2)
- N-hydroxylation
- rearrangement
(mediated by CYP)
how many metabolites are produced for most drugs? (2)
- less than 10 major metabolites
- possibly several minor metabolites
what are the problems with metabolites?
- they can accumulate and cause toxicity
what is phase I metabolism?
- chemically diverse small molecules are converted and transformed into generally more polar compounds
what are the phase I CYP reactions? (5)
- hydroxylation (aliphatic and aromatic)
- epoxidation
- dealkylation (N-, O-, S-)
- deamination
- oxidation (N-, S-)
what are the phase I non-CYP reactions? (2)
- oxidation
- hydrolysis
when a racemic mixture of warfarin is administered which isomer produces the anticoagulant response?
- S-warfarin
why is the S-warfarin the active form of warfarin? (2)
- S-warfarin has 1 major site of metabolism whereas R-warfarin has 3
- when there are more major site of metabolism it is broken down quicker and less efficient
what does the rate of second substitution depend on?
- the substrate
How can you slow down the rate of aromatic hydroxylation?
substitute phenol ring with a para-chlorine group (deactivate the ring).
What enzyme is used to catalyse codeine to morphine?
CYP2D6.
what effects the rate of aromatic hydroxylation?
- the more electron rich an electron ring the faster the rate of aromatic hydroxylation
what is a common approach to slow down or block aromatic hydroxylation?
- substitute phenyl ring with a para-fluorine or para-chlorine which deactivates the ring
what happens in oxidative N-dealkylation?
- C-H → C-OH → NH + C=O
what happens in oxidative O-dealkylation?
- C-H → C-OH → OH + C=O
what are poor metabolizers?
- people deficient in CYP2D6 and thus no activity
what does morphine undergo after its conversion from codeine?
- glucuronidation
for non-cyp oxidation what is MAO? (3)
- monoamine oxidase (in mitochondria)
- oxidatively deaminates endogenous neurotransmitters (eg dopamine)
- some drugs are designed to inhibit MAO used to affect balance of CNS neurotransmitters
for non-cyp oxidation what is FMO? (3)
- flavin monooxygenases
- family of enzymes that catalyse oxygenation of nitrogen, phosphorous, sulphur
for non-cyp oxidation what is xanthine oxidase? (2)
- allopurinol is a substrate for xanthine oxidase
- used for treatment of gout
what is an example of non-cyp hydrolysis? (2)
- ester hydrolysis (ester to carboxylic acid)
- pethidine metabolized by liver carboxyesterase to form carboxylic acid metabolite (no analgesic activity)
which is more chemically stable (longer half life) an ester or amine? (2)
- amine functional group is very stable and has a longer half life
- ester linkage readily undergoes ester hydrolysis
what happens in phase II metabolism?
- conjugation which results in more polar compounds being formed and are rapidly eliminated into urine and/or bile
what reactions do phase II metabolism include? (5)
- glucuronidation
- sulphation
- amino acids
- acetylation
- methylation
what enzyme does glucuronidation need?
- UDP-Glucuronosyl-Transferase (UDPGT)
what groups are conjugated in glucuronidation? (6)
- OH
- COOH
- NH2
- NR2
- SH
- CH
what happens in glucuronidation? (2)
- links the drug to still more polar molecules to render them even more easy to excrete
- adds C6H9O6
what happens in acetylation? (2)
- OH turns to C=O
- NH2 turns to NH
what is the solubility of sulphotranferase and where are they found? (2)
- they are soluble
- found in cell cytoplasms
what does the drug act as in sulphation?
- nucleophile (R-OH drug)
what are the two metabolites of paracetamol and their percentages? (2)
- paracetamol-glucuronide (60%)
- paracetamol-sulphate (35%)
what is the other 5% of paracetamol metabolised to?
- NAPQI
what happens to NAPQI during phase II metabolism and why? (3)
- glutathione conjugation
- prevents toxicity of oxidative metabolites after normal doses
- this mechanism is swamped after an overdose
what happens in a paracetamol overdose? (4)
- more paracetamol is shunted to the cytochrome P450 system to produce NAPQI
- hepatocellular stores of glutathione become depleted
- NAPQI reacts with cellular membrane molecules (including proteins and nucleic acids)
- resulting in hepatocyte damage and death
