Introduction To Biotranformation, Pharmacogenomics, And CLinical Drug Trials

Question 1

Biotransformation is what

Answer 1

Drug becomes changed to another substance

• usually to a more polar and water solvable substance that kidneys can excrete
• usually less pharmacodynamic hen parent drug

Question 2

Prodrug is what and example

Answer 2

Inactive drug that goes through biotransformation to become active
L-dopa——> dopamine

Question 3

Where do most biotransformations occur

Answer 3

In the liver before entering the blood stream = first pass biotransformation

Question 4

When is there no biotransformation

Answer 4

In route is parenterally (morphine needs as a high first pass effect and preferred as intravenous)

Question 5

Purpose of phase 1, phase 2

Answer 5

Phase 1 : inactivation of drug (more polar making, catabolic usually)
Phase 2 : improve water solubility (conjugation with some acid, usually anabolic)

Question 6

What are common conjugators

Answer 6

Glucuronic acid, sulfuric acid, acetic acid, animo acids

Question 7

Phase 1 enzymes

1. Examples
2. Location

Answer 7

1. CYP450s, FMO, mEH sEH

2. ER membranes of liver

Question 8

Biggest CYP

Answer 8

CYp3A4

Question 9

Phase 2 enzymes

1. Examples

Answer 9

1. many transferases : UGT, GST, NAT, TRMT, SULT

Question 10

Genetic differences that effect biotransformation can happen to what drug

Answer 10

1. Succinylcholine

2. Slow acetylator phenotype for N-acetransferase enzyme

Question 11

Non-genetic differences in drug effects examples

Answer 11

1. Enzyme induction : phenobarbital, chronic ethanol, aromatic hydrocarbons (tobacco smoke), rifampin, St. John’s wort (increase CYP3A4)
2. Enzyme inhibition : Grapefruit juice has higher affinity to CYP3A4 and other drug not metabolized as well
3. Age : hepatic BF slows, slower metabolism
4. Any diseases

Question 12

Acetaminophen try toxic levels causes

Answer 12

Delayed hepatotoxicity

Question 13

Acetaminophen metabolism

Answer 13

1. GSH conjugation ——> adds glutathione = mercapturic acid

2. When no glutathione is left ——> Nucleophilic cell macromolecules (toxic to liver)

Question 14

Alcohol and acetaminophen

Answer 14

Alcohol INDUCES CYPs, so you have more acetaminophen metabolism and more nucleophilic cell macromolecules made, higher chance of delayed hepatotoxicity

Question 15

Pharmacogenetics

Answer 15

Studying differences in drug response from allelic variation in genes (which can effect metabolism, efficacy, toxicity)

Question 16

Polymorphism

Answer 16

Variation in DNA sequence that is present with 1% frequency or greater in a population

Question 17

Polymorphism in CYP450s can result in

Phase 1 variations

Answer 17

Phase 1 variations = CYP variation

1. Absent or decreased : can accumulate toxic drug levels
2. Increased : undertreated risk

Question 18

Polymorphism in CYP450s can result in

Phase 2 variations

Answer 18

1. UDP- glycosyltransferase (GST) : gluconation
2. NAT : acetylation
3. Succinylcholine : methylation

Question 19

Variation in pharmacodynamics

Answer 19

1. G6PD deficiency (G6PD makes NADPH which makes GSH = protects cells), when you take some drugs there is oxidative damage leading to HEMOLYTIC ANEMIA that happens)
2. Ryanodine receptor mutation = MALIGNANT HYPERTHERMIA: when taking succinylcholine or inhalation anesthetics this causes elevated Ca+2 in muscles = muscle rigidity and high body temps, rhabdomyolysis

Question 20

Polygenic effects

Answer 20

Effect variations in both pharmacodynamics (drug target changes) and pharmacokinetics (metabolizing enzyme changes)
= Warfarin can do this is some people

Question 21

CYP2C9 and variations in it

Answer 21

Acts on Warfarin and NSAIDS has many variations

Can make slower metabolism of warfarin

Question 22

Vitamins K epoxide reductase (VKORC1) variations

Answer 22

Warfarin acts on this as an anticoagulant

Many variations on this = phase 2= higher sensitivity to warfarin

Question 23

Goals of animal testing

Answer 23

Toxicity to humans
Toxic mechanism and which are most toxic to monitor if further phases of trials
(Some adverse effects in humans cant be seen in animals)

Question 24

When testing a drug in vitro studies and giving it to animals

Answer 24

Lead compound : starting point look at potency, selectivity, pharmacokinetics

Question 25

When testing drug in clinical trials on humans

Answer 25

Investigational new drug (IND) : before starting clinical trials

Question 26

When drug is in marketing it had to first go through

Answer 26

New drug application (NDA) for FDA approval after clinical trials

Question 27

IRB

Answer 27

Makes sure right steps were taken

Question 28

To limit variable natural history and progression of disease in experimental subjects

Answer 28

Crossover design, large population of patients, time

Question 29

To limit presence of disease or other risk factors in experimental subjects

Answer 29

Drug use collections

Question 30

To limit variable subject and observational bias in experimental subjects

Answer 30

Placebo, single-blind, double blind

Question 31

How can endpoint in different studies of the same drug be different

Answer 31

1. One study can say A lowers LDL levels more then B (so they concluded that A should lower cardiovascular events = surrogate endpoint)
2. Other study says neither A or B lowers cardiovascular events