Pharmacology Drug Metabolism/Pharmacogenetics

Question 1

Major class of Phase 1 metabolism enzymes?

Answer 1

P450s

Question 2

What 3 P450 isoforms handle 90% of all drugs?

Answer 2

Cyp3A, Cyp2D6, Cyp2C9

Question 3

What percentage of drugs does Cyp3A handle?

Answer 3

50%

Question 4

What percentage of drugs does Cyp2D6 handle? What two major drug classes?
Are there important polymorphisms?

Answer 4

25%
anti-depressants* (tricyclics) and beta-blockers, others
Yes, poor and ultrafast metabolizers (poor=2 copies of slow; ultrafast=gene duplication of normal allele)

Question 5

What percentage of drugs does Cyp2C9 handle?
What major drug?
Are there important polymorphisms? Why is it so important?

Answer 5

15%
WARFARIN; phenytoin, several other classes
Yes. 2 alleles with low activity, *2 and 3 (3 is worse) with at least one copy of a variant in up to 31% of pts.
Warfarin is cleared almost exclusively by this Cyp and has a narrow therapeutic window with negative consequences at either range (not enough=clot, too much=bleeding)

Question 6

What are the common results of phase 1 metabolism?

Answer 6

drug undergoes oxidation, reduction, dealkylation, or hydrolysis

Question 7

What organ is the major site of drug metabolism?

What is the intracellular site of phase 1 and phase 2 metabolism?

Answer 7

Liver; but all tissues have SOME
phase 1: usually smooth ER, cytosolic face
phase 2: most cytosolic

Question 8

Flavin containing monooxygenases do what phase of metabolism?
What are their usual substrates?

Answer 8

Phase 1

More foreign and polar substrates compared to P450s, usually soft nucleophiles (N, S, P)

Question 9

How many FMO isoforms are there? What is the major one found in the liver?

Answer 9

FMO1-5; FMO3 is major isoform

Question 10

What is happening in phase 2 metabolism?

Answer 10

conjugation of drug/metabolite to an endogenous substrate molecule–> makes more polar, less toxic, and inactive

Question 11

What are 4 types (and each enzyme) of phase 2 conjugations that we need to know?

Answer 11

1. Glucuronidation–UGT enzyme
2. Acetylation–NAT
3. Sulfation–SULT
4. Glutathione–GST

Question 11

What are 2 other types of enzymes that do phase 1 metabolism?

Answer 11

Dehydrogenase and hydrolases ( cocaine, aspirin, lidocaine)

Question 12

What are some drug substrates of FMOs

Answer 12

Nicotine, cimetidine, spironolactone, ranitidine

Question 13

What is the significance of conjugation capacity? Which 2 phase 2 enzymes have a low conj capacity .

Answer 13

It refers to the amount of enzyme available to metabolize the drug, or it’s ability to be regenerated quickly.
SULT and GST have low conjugation capacity, can’t handle large amounts of the drug.

Question 14

What are some characteristics of glucuronidation? What are some drugs metabolized with this pathway?

Answer 14

UGT enzyme does.. Has a high conjugation capacity, it’s the most used.
Acetaminophen, morphine (activates), lorazepam

Question 15

What 3 major drugs does Cyp2C19 metabolize?

Answer 15

Omeprazole/Prilosec (PPI), phenytoin (anti-convulsant), clopidogrel (anti-platelet)

Question 16

What are the polymorphisms of Cyp2C19?

Answer 16

Poor, heterozygote, extensive metabolizer. Poor metabolizers have 2 copies of the slow allele. Heterozygotes have 32% decrease in active drug levels.

Question 17

What important drug does Cyp2C19 ACTIVATE? (administered drug is inactive)

Answer 17

Clopidogrel/Plavix-anti platelet commonly given after cardiac surgery/post MI

Question 18

Warfarin inhibits the activity of what complex needed to modify clotting factors?

Answer 18

Vitamin K Receptor (VKORC1)