Enzyme and Biotransformations

Question 1

Phase I reactions

Answer 1

Usually convert the parent drug by adding or unmasking a polar functional group (OH, SH, NH2)
PHASE i reactions can follow phase II reactions

Question 2

Phase II reactions

Answer 2

Some products of phase I reactions are not readily excreted
These are conjugated with endogenous substrates in a phase II reaction
Some parent drugs already have functional groups and are only conjugated by phase II

Question 3

Other sites of drug metabolism besides the liver

Answer 3

GI tract, lungs, skin, kidneys and brain

Question 4

What is required for microsomal drug oxidations?

Answer 4

P450, P450 Reductase, NADPH, and molecular oxygen

Question 5

Mechanism of P450 Drug Oxidation

Answer 5

Oxidized P450 binds to drug
NADPH donates electron to flavoprotein P450 Reductase
Sequential reduction of Oxidized P450 complex
Repeat step 2
Molecular oxygen reduced to form P450 complex activated O2
Activated oxygen transferred to drug to form oxidized product

Question 6

What are the important P450 Isoforms

Answer 6

1A2, 2A6, 2B6, 2C9, 2D6, 2E1, 3A4

Question 7

Isoform responsible for over 50% of liver drug metabolism

Answer 7

3A4

Question 8

CYP2D6 Mutations

Answer 8

Codeine, oxycodone, dextromethorphan, B-blockers, TCAs
Mutations that reduce activity in sweden and china
Mutation in east africa increase activity
Limited clinical significance
Reduced analgesia from codeine and oxycodone

Question 9

CYP2C19 Mutations

Answer 9

Inactivation of enzyme
Asians, and blacks
Omeprazole, clopidogrel, amitryptiline, imipramine, citalopram, diazepam, nelfinavir, phenytoin
Defects in CYP219 genotype lead to higher cure rate for H. Pylori

Question 10

Clopidogrel

Answer 10

anti-coagulant pro-drug used for platelet aggregation
Uses Cyp2c19
Omeprazole inhibits enzymes responsible for activation
Omeprazole may lower efficacy of clopidogrel
When not active platelets still highly active

Question 11

Phenytoin

Answer 11

Acted on by Many different enzymes

Question 12

Cyp2c9

Answer 12

Most polymorphisms reduce activity

S-warfarin, phenytoin, Iosartan

Question 13

Polymorphisms in Phase I enzymes

Answer 13

Dihydropyrimidine dehydrogenase: lead to impaired metabolism of 5-flourouracil (rare)
Pseudocholinesterase: Plasma ChE enzymes, extends action of succinylcholine (rare)

Question 14

N-acetyl transferases of liver

Answer 14

NAT1 and NAT2
NAT1 Responsible for acetylation of simple aromatic amines
NAT2 Acetylates polycyclic amines (Failure drives metabolism of Isoniazid down toxic route, also causes procainamide breakdown to lead to Lupus)

Question 15

Lupus and Procainamide

Answer 15

Occurs in 30% of people receiving prolonged procainamide treatment
Most common in caucasians and africans

Question 16

Drugs metabolized by NAT2

Answer 16

Isoniazid
Procainamide
Caffeine
Dapzone
Hydralazine
Histamine

Question 17

Clinical relevance of acetylation polys

Answer 17

greater risk to neuropathy and hepatitis
Faster ANA appearance in slow acetylators
Less K channel blockage by procainamide
Increased risk for cancer in smokers because carcinogens are at higher concentrations
Fast acetylators have increased risk for colon cancer

Question 18

TPMT

Answer 18

Metabolizes 6-mercaptopurine
Homozygous mutants lack activity
Causes increased HPRT activity

Question 19

Clinical consequences of TPMT mutations

Answer 19

6-MP is used in maintenace of ALL in kids
Increased toxic 6-TGN levels
Need to up dosage 15 fold

Question 20

MDR-1 polymorphism

Answer 20

Reduced MDR expression

Increased plasma levels of antiretrovirals and fexofenadine

Question 21

ADRB2 poly

Answer 21

Rapid densensitization by agonists in veins

Increased bronchodilator response

Question 22

5-LOX poly

Answer 22

Reduced incidence of asthma

No effect of 5-Lox inhibitors

Question 23

VKORC1

Answer 23

Affects sensitivity to Warfaring requiring larger dose

Plays role in regulation of blood clotting

Question 24

Warfarin metabolism

Answer 24

Cyp2c9 polys cause slow metabolism of warfarin causing bleeding problems
VKORC1 leads to insensitivity to warfarin