Introduction to Biotransformation, Pharmacogenetics and Clinical Drug Trials Flashcards
What substances are more readily excreted by the kidneys?
polar and water soluble products
3 consequences of biotransformation
inactivation
active compound–>active compound
activation
most occurs in liver
first pass effect
oral drugs undergo excessive biotransformation after absorption prior to entering circulation
limits the bioavailability of some drugs–alternative routes of administration must be explored
phases of biotransformation
phase I: biological inactivation of drug
phase II: improved water solubility and increased molecular weight
enhances elimination–conjugation
phase I reaction
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
phase II reaction
conjugation with endogenous substances (glucuronic acid, sulfuric acid, acetic acid)
improves water solubility and increase molecular weight
anabolic
phase I reaction products
generally more reactive and make be more toxic
phase I reaction enzymes
cytochrome p450s
FMOs (flavin containing monooxygenases)
epoxide hydrolyses (mEH, sEH)
most important CYP450 enzyme
CYP3A4–50% of biotransformation in drugs today
phase II enzymes
UGT (UDP-glucuronosyltransferase) GST (glutathione-S-transferase) NAT (N-acetyltransferase) TPMT (thiopurine methyltransferase) SULT (sulfotransferase)
Individuals differ in?
drug distribution
rates of drug metabolism and elimination
genetic factors biotransformation
polymorphisms in metabolizing enzymes
enzyme expression levels
genetic difference that affects biotransformation–slow acetylator phenotype for N-acetyltransferase enzyme
metabolized at slower rates–coffee, isoniazid (treats tb), hydrazine (treats hypertension)–leads to hepatotoxicity
50% of population
drug-drug interactions
enzyme induction
enzyme inhibition
inducers of CYP450
phenytoin (anticonvulsant) chronic ethanol (CYP2E1) aromatic hydrocarbons--tobacco smoke (benzopyrene) rifampin (anti-tb) phenobarbital
other non-genetic difference in biotransformation
age disease states (liver, cardiac disease)
grapefruit juice effect
a compound in grapefruit juice inhibits certain CYP450 enzymes–CYP3A4
Allopurinol and mercaptopurine
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
metabolism to toxic products example
acetaminophen--induced hepatotoxicity when overdose--glucuronidation and sulfating pathways are saturated P450 pathways become more important hepatic GSH is depleted toxic metabolites accumulate
drug-response variability–variations can occur in?
pharmacokinetics–rate which body absorbs, transports, metabolizes, excretes a drug/metabolites
pharmacodynamics–allelic variation in a drugs downstream targets
variations in phase I reactions
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
variations in phase II reactions
polymorphisms in
UDP glycosyltransferase and camptothecin
N-acetyl transferase and isoniazid
cholinesterase and succinylcholine
glucose 6 P dehydrogenase deficiency
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
Ryanodine receptor mutations
inhalational anesthetics, succinylcholine
elevation of Ca in sarcoplasm of muscle leads to muscle rigidity, elevation of body temperature, malignant hyperthermia
Genetic variation in both pharmacokinetics and pharmacokinetics
variations at multiple gene loci (polygenic effects)
warfarin polymorphisms in enzymes and in drug target
drug development and clinical trials steps
lead compound–in vitro studies
animal testing
clinical testing–phase 1-3
phase 4–postmarketing surveillance
clinical trial endpoints
measured to assess a drugs effect (Ex–BP is endpoint for testing an antihypertensive agent)
hepatic enzyme activity in neonate
have decreased conjugating activity
hyperbilirubinemia in newborn (can’t conjugate bilirubin–UDP glucuronosyl transferase levels are low)
Genetic difference that affects biotransformation–succinylcholine
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
