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Flashcards in Drug Metabolism Deck (23):
1

Describe the principle consequences of drug metabolism.

- increased water-solubility
- increased potential for excretion by bile or urine

2

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

3

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

4

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

5

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

6

Consequences of drug metabolism:
- lipophilic drugs
- active drugs
- prodrugs/inactive
- toxic xenobiotics.

- lipophilic => polar
- active => inactive or active metabolite
- prodrug => active
- toxic => nontoxic

7

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

8

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

9

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)

10

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)

11

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

12

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

13

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)

14

Describe the Phase I metabolism of omeprazole.

- major pathway: via CYP2C19 (90%)
- minor pathway: via CYP3A4 (10%)

15

Describe the Phase I metabolism of omeprazole.

- major pathway: via CYP2C19 (90%)
- minor pathway: via CYP3A4 (10%)

16

Characterize a Phase II reaction.

- attaches a large endogenous polar compound to make drug more water soluble and easily excretable
- faster than Phase I
- takes place in cytoplasm (except glucuron on ER membrane)
- mostly inactivates (except minoxidil and morphine)
- drug-conjugate cannot freely diffuse across membranes
- some drugs with OH, COCH, NH2 groups can directly undergo Phase II
- glucuronidation is most common; increases excretability by bile and urine

17

Phase II reactions require:

- drug with suitable functional group
- specific enzymes
- activated high-energy cofactor/cosubstrate

18

List the enzymes required to carry out the following phase II reactions:
- glucuronide conjugations
- glutathione conjugations
- sulfate conjugations
- acetylation
- methylation

- glucuronide: UDP-glucuronosyltransferase (UGT)
- glutathione: glutathione S-transferase (GST)
- sulfate: sulfotransferase (ST)
- acetylation: N-acetyltransferase (NAT)
- methylation: methyltransferase (MT)

19

List the enzymes required to carry out the following phase II reactions:
- glucuronide conjugations
- glutathione conjugations
- sulfate conjugations
- acetylation
- methylation

- glucuronide: UDP-glucuronosyltransferase (UGT)
- glutathione: glutathione S-transferase (GST)
- sulfate: sulfotransferase (ST)
- acetylation: N-acetyltransferase (NAT)
- methylation: methyltransferase (MT)

20

Which drugs are eliminated by the kidney vs bile?

- most drugs undergo renal clearance: water-soluble unbound drugs are freely filtered into the glomerulus or actively transported into the tubules => URINE
- larger, lipophilic drugs are excreted in the bile (but undergo enterohepatic recirculation)

21

How do CYP450 inducers affect drug metabolism?

- act as ligands => bind to transcription factors => increase transcription of CYP genes => induces expression of CYP enzymes
- increases metabolism of drugs that are CYP substrates => increased clearance => decreases drug activity => decreases drug concentration below critical therapeutic dose => treatment failure
- EXCEPTION: prodrugs become more active because increased metabolism increases amount of active drug

22

How do CYP450 inhibitors affect drug metabolism? What are the types of inhibition?

- decrease metabolism => increased concentration of drug => potential for toxicity (especially for drugs with narrow therapeutic window
- drugs can be substrates of one and inhibitors of another CYP enzymes or the same CYP enzymes

Types
- reversible: competitive, allosteric
- irreversible: suicide inhibitor (covalent binding)

23

Define gray baby syndrome.

- neonates: conjugating enzyme deficiency leads to gray baby syndrome when given chloramphenicol due to buildup of chloramphenicol oxidation (phase I) metabolite => circulatory collapse and cyanosis