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Pharm Block 1 > Drug Metabolism > Flashcards

Drug Metabolism Flashcards

1
Q

Define drug metabolism

A

the enzymatic catalyzed conversion of a drug or xenobiotic compound to their metabolites

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2
Q

What does drug metabolism primarily do?

A

converts lipophilic drugs into more hydrophilic polar metabolites, which enhances drug excretion and elimination (liphophilic drugs are readily reabsorbed in the kidney

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3
Q

What is the major organ site of drug metabolism?

A

The liver, although the intestine also plays a major role (other cell types involved include skin, kidney, lung, brain)

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4
Q

What are the subcellular sites of drug metabolism?

A

CYP450 and some others associated with ER, most others in the cytoplasm

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5
Q

What organs are involved in first pass metabolism?

A

GI + hepatic metabolism

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6
Q

What are the phase I reactions?

A

oxidation, reduction, hydrolysis

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7
Q

What does phase I reactions do?

A

introduces or unmasks a small functional group on the drug (eg OH), which makes it more polar and alters the function of the drug

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8
Q

What are phase II reactions?

A

introduces a large highly polar endogenous functional group onto the drug metabolite (eg glucuronic acid, sulfuric acid, acetic acid, amino acid), often via the functional group created during phase I reactions

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9
Q

What does phase II reactions do?

A

typically inactivates the drug and makes it highly polar, enhancing drug excretion

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10
Q

What are the reduction reactions in Phase I?

A

Azo reductions
Nitro reductions
Carbonyl reductions

(CAN reductions)

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11
Q

What are the hydrolysis reactions in Phase I?

A

Ester
Amid
Epoxide

(EpAmEs hydrolysis)

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12
Q

What enzymes do hydrolysis reactions?

A

Epoxide Hydrolases

Carboxylesterases

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13
Q

What enzymes do reduction reactions?

A

NADPH-cytochrome P450 reductase

Alpha-ketoreductases

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14
Q

What does most of the oxidative reactions?

A

cytochrome P450 - does ~75% of all phase I reactions

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15
Q

What are some other enzymes that do oxidative reactions?

A

flavin-containing monooxygenases
monoamine oxidase
alcohol dehydrogenases
aldehyde dehydrogenases

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16
Q

What are the characteristics of CYP450?

A

has O2 binding heme group

catalyzes redox reaction involving O2

oxidizes drug and NADPH simultaneously

membrane bound on ER

contains iron containing heme cofactor

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17
Q

What are the substrates for CYP450?

A

oxidation of lipophilic substrates - xenobiotics, drugs, and endogenous substrates

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18
Q

Where is the highest level of expression of CYP450?

A

liver and GI tract, low levels in lung, kidney, CNS, others

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19
Q

What are the 12 CYPs responsible for metabolism of essentially all xenobiotics and drugs?

A

CYP1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2D6, 2E1, 3A4, 3A5

20
Q

What are the most active CYP drugs, and which one is responsible for most metabolism?

A

most active are CYP2C, CYP2D, CYP3A

CYP3A4 accounts for metabolism of over 50% of clinically used drugs

21
Q

What does CYP450 reactions require?

A

drug substrate, molecular O2
NADPH
NADPH-CYP450 oxidoreductase

22
Q

What reactions do CYP450 enzymes catalyze?

A

hydroxylations, epoxidations, N-, S-oxidations, O-, S-, N-dealkylations, daminations, desulfurations, dechlorinations

23
Q

What does it mean that CYP450 is promiscuous?

A

they can metabolise multiple structurally distinct molecules

a single compound can be metabolized by multiple CYP450 enzymes (different rates)

CYP450s can metabolize a single drug at multiple different positions on the molecule

a single CYP450 can catalyze multiple different chemical reactions

24
Q

What is the redundancy of metabolism?

A

typically, most drugs are metabolized by one or a few enzymes (limiting redundancy)

25
Q

What are the characteristics of phase II drug metabolism?

A

catalytic rate is significantly faster that phase I

reactions take place in the cytoplasm (except glucocoronidation - ER membrane)

usually inactivates drug activity

creates highly polar drug-conjugate

enhances drug elimination in urine or bile

26
Q

What is unique about morphine and isoniazid, in regards to their metabolism?

A

some parental drugs that contain OH, COOH, or NH2 groups can directly undergo phase II metabolism without phase I preceding it

27
Q

What is required for phase II reaction?

A

drug substrate with suitable functional group

specific enzyme

an activated high energy cofactor

28
Q

What is the most frequent phase II reaction?

A

glucuronidation (using UDP-glucuronic acid and UDP-glucuronosyltransferase (UGT))

29
Q

what are prodrugs?

A

inactive compounds that are metabolized in the body to their active forms (carbamazepine, irinotecan, codeine, prednisone)

30
Q

What are the advantages of a prodrug?

A

when the prodrug has a better pharmacokinetic profile than its active metabolite

solubility, absorption, stability, toxicity, etc

31
Q

What organ accounts for the excretion of most drugs?

A

the kidney

Unbound water soluble polar drug metabolites are either filtered or actively secreted into the proximal tubules and excreted in the URINE

32
Q

Where else are drugs (both lipophilic and polar) excreted?

A

excreted in the bile

33
Q

What is a result of drugs that are excreted in the bile?

A

enterohepatic recirculation - can prolong the pharmacological effect of drugs

bacterial enzymes in the GI tract can hydrolyze drug-conjugates allowing for drugs to be reabsorbed and enter the circulation again where they undergo further hepatic metabolism

34
Q

How can drugs affect the metabolism of other drugs?

A

induction or inhibition of CYP450 enzymes

35
Q

What are some drugs/compounds that induce CYP450?

A

rifampin, phenytoin, phenobarbital, carbamazepine, glucocorticoids, pioglitazone, & St. John’s wort all induce 3A4

36
Q

What are the results of CYP450 induction?

A

increases metabolism of CYP450 enzyme substrates

decreases drug activity (or increases in the case of a prodrug)

increases drug clearance

can reduce drug concentration below a critical therapeutic dose (treatment failure)

37
Q

What are the results of CYP450 inhibition?

A

decrease drug metabolism resulting in an increase in the concentration of drug

potential for toxicity- especially with drugs that have a narrow therapeutic window!

38
Q

What are some important inhibitors of CYP3A4?

A 
Fluconazole (M)
Ketoconazole (S)
Itranaconazole (S)
Ritonavir (S)
Erthyromycin (M)
Clarithromycin (S)

Grapefruit juice (S)

39
Q

How does grapefruit juice increase the bioavailability of drugs metabolized by CYP3A4?

A

CYP3A4 is expressed in the GI tract and metabolizes drugs during the absorption process -decreasing their bioavailability (part of the first pass effect)

Grapefruit juice has compounds that inhibit 3A4 in enterocytes, thereby decreasing 3A4 metabolism of drug in the GI tract (No effect on hepatic CYP3A4)

40
Q

How does age affect drug metabolism?

A

decreased phase I metabolism in elderly (30-40 dose reduction)

41
Q

How does pregancy affect drug metabolism?

A

increases 2C9, 2D6, 3A4

decreases 1A2, 2C19

42
Q

how does race/ethnicity affect drug metabolism?

A

different polymorphic variants

43
Q

how does diet/environment affect drug metabolism?

A

grapefruit juice/others can inhibit CYP450 enzymes (affects bioavailability, NOT half life, inhibits intestinal 3A4, NOT hepatic 3A4)

St Johns Wort induces CYP 3A4 expression

cig smoke, charbroiled foods, cruciferous veggies all induce CYP1A2

chronic alcoholism induces CYP2E1

44
Q

How does disease affect drug metabolism?

A

diseases that affect the liver/blood flow to liver

inflammatory cytokines decrease expression of many CYP450s

45
Q

how does drug interactions affect drug metabolism?

A

induction/inhibition of CYP450

drugs can induce the enzymes responsible for their own metabolism, therefore reducing levels of active drug over time’

some drugs may compete for the same endogenous conjugation substrate

46
Q

How does genetics affect drug metabolism?

A

many enzymes involved in drug metabolism are polymorphic

individuals can express different enzyme alleles with different activities and expressions

results in individual-individual differences in the efficiency of drug metabolism and drug responses

Pharm Block 1 (8 decks)

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