Drug Metabolism Flashcards
Describe the principle consequences of drug metabolism.
- increased water-solubility
- increased potential for excretion by bile or urine
List the major anatomical and subcellular locations involved in drug metabolism.
organs
- LIVER, small intestine
- skin, lung, kidney, brain
subcellular
- CYP450 is in the ER
- other enzymes in the cytoplasm
Describe the first pass effect and how it contributes towards determining drug bioavailability.
GI + hepatic metabolism = first pass effect
- 100% of dose enters GI tract => CYP/PhaseII occurs in GI tract => 70% of drug (and metabolites) go to portal circulation => CYP/PhaseI and II occurs in the liver => 15% enters systemic circulation
- low bioavailability with oral administration vs 100% of IV
Describe the major features of Phase I and Phase II metabolic reactions. How do they contribute towards modification of drug activity and elimination?
Phase I - redox, hydrolysis
- uncovers or adds polar functional group
- alters function (decrease, increase, unchanged)
Phase II - conjugation (acetic, sulfa, amino, glucuronic)
- adds large polar endogenous functional group
- more water-soluble
- inactive
- easier to excrete
List the major types of enzymatic reactions and enzymes involved in Phase I and II metabolism
Phase I
- oxidation, hydroxylation, deamination, desulfurations, dechlorinations, epoxidations via CYPs
Phase II
- acetylation
- sulfation
- amination
- glucuronylation
Consequences of drug metabolism:
- lipophilic drugs
- active drugs
- prodrugs/inactive
- toxic xenobiotics.
- lipophilic => polar
- active => inactive or active metabolite
- prodrug => active
- toxic => nontoxic
Describe the major features of CYP450 enzymes and the reactions they perform.
CYP450 - microsomal mixed-function oxidases
- microsomal: membrane bound enzyme located on ER
- mixed-function: can have 2 substrates simultaneously
- oxidases: catalyzes redox reaction with O2 (lipophilic substrates)
- contains O2 binding heme group to transfer O2 to substrates
Describe the principle differences between the metabolism of a typical drug and a prodrug.
- require metabolism to be activated (Phase I): during this time of activation, some of the metabolite performs its action
- active metabolite is further inactivated and then undergoes Phase II
- have better pharmacokinetics than the active compound
Describe how enterohepatic drug recirculation influences the elimination and pharmacokinetic parameters of drugs that are excreted in the bile.
- drugs enter portal circulation => metabolized in the liver => stored in gallbladder for release into GI tract with bile => gut microbiota enzymes cleave drug-conjugates released with bile => cleaved drugs are reabsorbed into portal circulation => further hepatic metabolism
- reoccurs until drug is completely inactivated or excreted by kidney or bile (feces)
- prolongs pharmaceutical effect by reducing clearance, extending half-life, increasing AUC (inverse relationship with clearance)
Describe the 2 principle mechanisms underlying metabolic drug-drug interactions and give specific examples of each.
induction of CYP450 enzymes (ex: inducers of CYP3A4)
- rifampin
- carbamazipine
- phenobarbital
- phenytoin
- glucocorticoids
- pioglitazone
- St. John’s Wart
inhibition of CYP450 enzymes
- fluconazole (M)
- ketoconazole (S)
- itranacanazole (S)
- ritonavir (S)
- erythromycin (M)
- clarithromycin (S)
- omeprazole
- grapefruit juice (S)
- cyclosporine (W)
- cimetidine (W)
- amiodarone (M)
- diltiazem (M)
- verapamil (M)
Describe how grapefruit juice consumption can affect metabolism of certain drugs.
CYP3A4 inhibitor => increases bioavailability of CYP3A4 substrates
- no effect on hepatic CYP3A4, only enterocyte (GI) CYP3A4)
- more drug (bioavailable) reaches liver and systemic circulation
==> increased drug bioavailability
==> increased therapeutic effect
==> increased potential for toxicity
- 1 glass can inhibit for 24-48 hours
Describe the principle factors influencing drug metabolism.
Age
- neonates (gray baby)
- elderly: decreased activity of Phase I metabolism => reduce dose
Pregnancy
- some enzymes increase activity, some decrease
Race/Ethnicity
- polymorphisms
Diet/Environment
- grapefruit juice is an inhibitor
- St. John’s wart is an inducer
- chemicals in cigarettes, char-broiled, cruciferous vegetables are inducers (smokers need higher doses of CYP1A2 substrate drugs; ex: theophylline, antidepressants)
- chronic alcohol induces CYP2E1
Disease
- inflammatory cytokines decrease CYP450 expression
- liver function
Metabolic Drug Interactions
Drug-Endogenous Interactions
- competition for CYP substrates
Genetics
- polymorphic enzymes lead to individual differences in metabolism and response
Describe the promiscuity and redundancy of CYP enzymes.
- one drug can be metabolized by multiple CYPs (ex: citalopram)
- one drug can be metabolized by the same CYP with different reactions (ex: CYP3A4 hydroxylates and N-demethylates clarithromycin)
- a single CYP can carry out multiple different reactions
- most drugs only interact with one or a few CYP enzymes (limited redundancy)
Describe the Phase I metabolism of omeprazole.
- major pathway: via CYP2C19 (90%)
- minor pathway: via CYP3A4 (10%)
Describe the Phase I metabolism of omeprazole.
- major pathway: via CYP2C19 (90%)
- minor pathway: via CYP3A4 (10%)
