Pharmacogenetics, Drug Metabolism

Question 1

what are the 2 major routes of drug elimination

Answer 1

1. renal excretion through the kidney unchanged - small or polar drugs
2. metabolism into more readily excretable metabolites - lipophilic drugs, which can pass through membranes

Question 2

what kind of drugs are readily excreted through the kidney

Answer 2

small molecular size, polar drugs

lipophilic drugs are able to pass through membranes and are reabsorbed from kidney

Question 3

what is the purpose of drug metabolism

Answer 3

biotransformation of drugs to more polar and hence more readily excretable products

most drug metabolism reactions are chemical reactions catalyzed by endogenous enzymatic systems of body

Question 4

primary organ of drug metabolism and effect of this on oral administration

Answer 4

liver - where oral drugs are transported first via portal system

first pass effect: drug undergoes metabolism before reaching systemic circulation, can limit bioavailability

Question 5

phase I vs phase II drug metabolism reactions

Answer 5

Phase I (Functionalization): introduce or expose a polar functional group on parent compound

Phase II (Conjugation): coupling of endogenous compounds to phase I metabolites to yield highly polar (but chemically inactive) conjugates —> promotes elimination

Question 6

Phase I (functionalization) drug reactions are catalyzed by …

(describe these enzymes)

Answer 6

cytochrome P450 (CYP) enzymes: catalyze oxidative reactions to introduce or expose polar functional group (OH, COOH, NH2, SH) on parent compound

CYPs are heme-containing promiscuous (low specificity) enzymes

CYPs are slow enzymes

Question 7

how is nomenclature used to describe type of CYP enzymes

Answer 7

1. gene families designated by Arabic numerals (ex - CYP3)
2. subfamilies are designated by capital letters (ex - CYP3A)
3. individual genes are designated by Arabic numerals (ex - CYP3A4)

Question 8

what is the role of these enzymes:
CYP3A4, CYP2C9, CYP1A2, CYP2E1, CYP2D6, and CYP2C19

and which one is most active

Answer 8

major forms of CYP enzymes in human liver for drug and xenobiotic metabolism (Phase I)

CYP3A4 accounts for most of metabolism of clinically prescribed drugs that undergo hepatic metabolism

Question 9

Phase II (conjugation) drug metabolism reactions are catalyzed by ____

Answer 9

specific transferase enzymes

reactions include: glucuronidation, sulfation, N-acetylation, methylation, glutathione conjugation

[remember that CYP enzymes of Phase I are promiscuous - low specificity]

Question 10

glucuronidation vs glutathione conjugation

Answer 10

both important Phase II (conjugation) drug metabolism reactions

glucuronidation: most common, catalyzed by UDP-glucuronosyltransferase (UGT)

glutathione conjugation: conjugation of reactive electrophilic compounds with tripeptide glutathione, catalyzed by glutathione-S-transferase (GST), major detox pathway for drugs and carcinogens

Question 11

isoniazid (INH) and its metabolism

Answer 11

anti-tubercular drug with hepatotoxic metabolite

metabolism: Phase II acetylation followed by Phase I hydrolysis, which yields acetylhydrazine

acetylhydrazine is then detoxified by another Phase II reaction - glutathione conjugation

(flow: Phase II —> I —> II)

Question 12

acetaminophen and its metabolism

Answer 12

aka Tylenol, undergoes both Phase I and Phase II metabolism

Phase II: most of metabolism, glutathione conjugation

but, some undergoes Phase I hydroxylation —> resulting metabolite is hepatotoxic

if recommended dosage is exceeded, glutathione system is overwhelmed and permanent liver damage ensues - even if parent drug is removed because metabolite is already in system and cannot be removed

Question 13

major genetic factor affecting drug metabolism

Answer 13

polymorphisms: affecting a variant of a gene

affects metabolic rate

Question 14

how does a polymorphism in NAT2 gene affect drug metabolism

Answer 14

NAT2 = N-acetyltransferase 2
catalyzes Phase II (conjugation) metabolism of isoniazid (INH)

patients with 2 alleles of “slow” NAT2 exhibit “poor metabolizer” phenotype and INH accumulates —> adverse reactions

Question 15

in newborns, Phase I and II metabolic reactions occurs [faster/slower]

Answer 15

SLOWER than in adults

Question 16

what biological changes decrease overall drug metabolism (esp. CYP) in elderly? (3 things)

Answer 16

age-related decreases in liver mass, hepatic enzyme activity, hepatic blood flow

Question 17

drug metabolism is affected in pregnancy because of induced expression of ____ and _____

how is dose effected

Answer 17

induced expression of UGT (Phase II, glucuronidation) and CYP (phase I) enzymes, particularly in 2nd and 3rd trimesters

drug dose needs to be HIGHER to be as effective

Question 18

how are drug doses adjusted for patients with hepatitis, cirrhosis, cancer, and cardiac disease?

Answer 18

dose is lower

cardiac disease limits blood flow to liver, impairs transport of drug

Question 19

certain environmental factors induce expression of CYP enzymes (charcoal-broiled food, cigarette smoking, chronic alcohol consumption, certain herbal remedies)

how should dose be adjusted

Answer 19

dose should be HIGHER because there are more Phase I metabolic enzymes (CYP)

and vice versa - dose should be lower for patients with environmental factors that lower CYP enzymes (grapefruit juice)

Question 20

You have a patient who is taking multiple drugs. Drug A induces Phase I CYP enzymes and Phase II transferase enzymes.

How should the dosage of Drug B be adjusted?

Answer 20

Drug B should be administered at a higher dose

drug-drug interactions