Drug Metabolism Flashcards
drug metabolism
- chemical transformation of drug within living organism
- =drug biotransformation
- most =enzyme based but some arent
- makes drugs more hydrophillic which is needed for excretion
drug metabolism and inactivation
- change active drug to inactive
- change lipid soluble to less lipid soluble to facilitate excretion via kidney
- chemical modification of drug terminates activity
activation and drug metabolism
- metabolism can change an inactive drug to an active metabolite or a toxic metabolite
- can maintain active drug to active metabolite
cellular level of drug metabolism
- hepatocyte (cytoplasm)
- intestinal epithelial cell
- mitochondria
- ER
- lysosome
- plasma mb
phase I reactions
- activity = equal, lower, or higher
- functional groups = NH (amine), OH (hydroxyl), or SH (sulfhydral)
phase II reactions
- enzymes are often in the cytoplasm
- activity = lower
- glucuronic acid
- glutathione
- sulfate group
- acetyl group
Main phase I reactions
- microsomal oxidation: hydroxylation reactions
- non-microsomal oxidation - alcohol oxidation
- hydrolysis reactions: esterases and amidases
cytochrome P450 enzymes
- family of enzymes (57 isoforms)
- mainly found in ER (liver and intestine)
- mixed function oxidase (MFO) system used in microsomal oxidations of phase I reactions
microsomal fraction
- isolated by tissue homogenization and differential centrifugation
- pellet - vesicles formed from ER mb : microsomes
- useful for in-vitro studies
- assign P450 enzymes to drug: promiscuity
cytochroe P450 cycle
- RH + O2 + NADPH + H+ —— ROH + H2O + NADP+
- oxygen gets incorporated into hydroxyl group and water
- Iron involved in redox reaction
how is alcohol metabolized
- alcohol dehydogenase mainly (non-microsomal oxidation)
- some by catalase and CYP2E1
If status of an enzyme changes, that will adjust how things are ______
metabolized
PABA
- PABA is a metabolite of esterase and amidase reactions
- structurally similar to sulfonamides (antimicrobial)
- will compete with sulfonamide for drug site of action and lead to reduced therapeutic effectiveness
oxidation reactions (phase I) often precede conjugation (phase II) because the generated _____ group during phase I reaction is easily conjugated with several compouds
hydroxyl group
factors affecting drug metabolism
- drug-age interactions (differential expression of enzymes)
- drug-drug incompatibilities (competitive inhibition, induction=pharmacokinetic tolerance)
- drug-endogenous substrate interactions (competition with endogenous substrate)
- drug disease interaction (liver disease= impact on microsomal oxidases, cardiac disease = impact on hepatic blood flow)
- drug-genetic interactions (gene mutations, different metabolism rates)
induction and metabolism
- usually involves CYP450s (enhanced rate of synthesis or reduced rate of degradation)
- can be affected by environ pollutants, tobacco smoke, charcoal broiled meat
inhibition and metabolism
- some drugs can inhibit drug metabolizing enzymes
- two drugs metabolized by the same enzymes
competitive inhibition
- one drug can compete for enzyme with co-administered drug
- reversible
non-competitive inhibition
- permanent inhibition of enzyme
- covalent modification
- irreversible
active drug (parent drug)
- very lipid soluble
- less polar
- less ionized
- weak electrolyte
- more able to penetrate mb
inactive drug (drug metabolite)
- less lipid soluble
- more polar
- more ionized
- strong electrolyte
- less able to penetrate cell mb
