Enzyme and Biotransformations Flashcards
Phase I reactions
Usually convert the parent drug by adding or unmasking a polar functional group (OH, SH, NH2)
PHASE i reactions can follow phase II reactions
Phase II reactions
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
Other sites of drug metabolism besides the liver
GI tract, lungs, skin, kidneys and brain
What is required for microsomal drug oxidations?
P450, P450 Reductase, NADPH, and molecular oxygen
Mechanism of P450 Drug Oxidation
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
What are the important P450 Isoforms
1A2, 2A6, 2B6, 2C9, 2D6, 2E1, 3A4
Isoform responsible for over 50% of liver drug metabolism
3A4
CYP2D6 Mutations
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
CYP2C19 Mutations
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
Clopidogrel
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
Phenytoin
Acted on by Many different enzymes
Cyp2c9
Most polymorphisms reduce activity
S-warfarin, phenytoin, Iosartan
Polymorphisms in Phase I enzymes
Dihydropyrimidine dehydrogenase: lead to impaired metabolism of 5-flourouracil (rare)
Pseudocholinesterase: Plasma ChE enzymes, extends action of succinylcholine (rare)
N-acetyl transferases of liver
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)
Lupus and Procainamide
Occurs in 30% of people receiving prolonged procainamide treatment
Most common in caucasians and africans
Drugs metabolized by NAT2
Isoniazid Procainamide Caffeine Dapzone Hydralazine Histamine
Clinical relevance of acetylation polys
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
TPMT
Metabolizes 6-mercaptopurine
Homozygous mutants lack activity
Causes increased HPRT activity
Clinical consequences of TPMT mutations
6-MP is used in maintenace of ALL in kids
Increased toxic 6-TGN levels
Need to up dosage 15 fold
MDR-1 polymorphism
Reduced MDR expression
Increased plasma levels of antiretrovirals and fexofenadine
ADRB2 poly
Rapid densensitization by agonists in veins
Increased bronchodilator response
5-LOX poly
Reduced incidence of asthma
No effect of 5-Lox inhibitors
VKORC1
Affects sensitivity to Warfaring requiring larger dose
Plays role in regulation of blood clotting
Warfarin metabolism
Cyp2c9 polys cause slow metabolism of warfarin causing bleeding problems
VKORC1 leads to insensitivity to warfarin
