Introduction to Biotransformation, Pharmacogenetics and Clinical Drug Trials

Question 1

What substances are more readily excreted by the kidneys?

Answer 1

polar and water soluble products

Question 2

3 consequences of biotransformation

Answer 2

inactivation
active compound–>active compound
activation
most occurs in liver

Question 3

first pass effect

Answer 3

oral drugs undergo excessive biotransformation after absorption prior to entering circulation
limits the bioavailability of some drugs–alternative routes of administration must be explored

Question 4

phases of biotransformation

Answer 4

phase I: biological inactivation of drug
phase II: improved water solubility and increased molecular weight
enhances elimination–conjugation

Question 5

phase I reaction

Answer 5

introducing or unmasking a functional group–metabolite becomes more polar
oxidation, reduction, hydrolysis
catabolic
products can be more reactive and sometimes more toxic than parent drug

Question 6

phase II reaction

Answer 6

conjugation with endogenous substances (glucuronic acid, sulfuric acid, acetic acid)
improves water solubility and increase molecular weight
anabolic

Question 7

phase I reaction products

Answer 7

generally more reactive and make be more toxic

Question 8

phase I reaction enzymes

Answer 8

cytochrome p450s
FMOs (flavin containing monooxygenases)
epoxide hydrolyses (mEH, sEH)

Question 9

most important CYP450 enzyme

Answer 9

CYP3A4–50% of biotransformation in drugs today

Question 10

phase II enzymes

Answer 10

UGT (UDP-glucuronosyltransferase)
GST (glutathione-S-transferase)
NAT (N-acetyltransferase)
TPMT (thiopurine methyltransferase)
SULT (sulfotransferase)

Question 11

Individuals differ in?

Answer 11

drug distribution

rates of drug metabolism and elimination

Question 12

genetic factors biotransformation

Answer 12

polymorphisms in metabolizing enzymes

enzyme expression levels

Question 13

genetic difference that affects biotransformation–slow acetylator phenotype for N-acetyltransferase enzyme

Answer 13

metabolized at slower rates–coffee, isoniazid (treats tb), hydrazine (treats hypertension)–leads to hepatotoxicity
50% of population

Question 14

drug-drug interactions

Answer 14

enzyme induction

enzyme inhibition

Question 15

inducers of CYP450

Answer 15

phenytoin (anticonvulsant)
chronic ethanol (CYP2E1)
aromatic hydrocarbons--tobacco smoke (benzopyrene)
rifampin (anti-tb)
phenobarbital

Question 16

other non-genetic difference in biotransformation

Answer 16

age
disease states (liver, cardiac disease)

Question 17

grapefruit juice effect

Answer 17

a compound in grapefruit juice inhibits certain CYP450 enzymes–CYP3A4

Question 18

Allopurinol and mercaptopurine

Answer 18

allopurinol treated uric acid by inhibiting xanthine oxidase
xanthine oxidase–key enzyme in biotransformation of mercaptopurine (immunosuppressive agent in cancer)
cadmic–prolongs duration of mercaptopurine–enhances its effects

Question 19

metabolism to toxic products example

Answer 19

acetaminophen--induced hepatotoxicity
when overdose--glucuronidation and sulfating pathways are saturated
P450 pathways become more important
hepatic GSH is depleted
toxic metabolites accumulate

Question 20

drug-response variability–variations can occur in?

Answer 20

pharmacokinetics–rate which body absorbs, transports, metabolizes, excretes a drug/metabolites
pharmacodynamics–allelic variation in a drugs downstream targets

Question 21

variations in phase I reactions

Answer 21

polymorphisms in CYP450 can result in absent, decreased, or increased enzyme activity
poor metabolizers–at risk for accumulating toxic drug levels
ultrafast metabolizers at risk for under treatment with inadequate doses

Question 22

variations in phase II reactions

Answer 22

polymorphisms in
UDP glycosyltransferase and camptothecin
N-acetyl transferase and isoniazid
cholinesterase and succinylcholine

Question 23

glucose 6 P dehydrogenase deficiency

Answer 23

most common disease producing enzyme defect in humans
G6PD makes NADPH which reduces glutathione
reduced glutathione protects cells against oxidative damage
deficiency–>oxidative damage–hemolytic anemia in presence of oxidants

Question 24

Ryanodine receptor mutations

Answer 24

inhalational anesthetics, succinylcholine

elevation of Ca in sarcoplasm of muscle leads to muscle rigidity, elevation of body temperature, malignant hyperthermia

Question 25

Genetic variation in both pharmacokinetics and pharmacokinetics

Answer 25

variations at multiple gene loci (polygenic effects)

warfarin polymorphisms in enzymes and in drug target

Question 26

drug development and clinical trials steps

Answer 26

lead compound–in vitro studies
animal testing
clinical testing–phase 1-3
phase 4–postmarketing surveillance

Question 27

clinical trial endpoints

Answer 27

measured to assess a drugs effect (Ex–BP is endpoint for testing an antihypertensive agent)

Question 28

hepatic enzyme activity in neonate

Answer 28

have decreased conjugating activity

hyperbilirubinemia in newborn (can’t conjugate bilirubin–UDP glucuronosyl transferase levels are low)

Question 29

Genetic difference that affects biotransformation–succinylcholine

Answer 29

neuromuscular blocking
broken down by cholinesterase’s
its can have polymorphisms in the enzyme that breaks down succinylcholine so it breaks it down slower
relevant when having to intubate a pt bc diaphragm is still paralyzed