Drug Metabolism Flashcards
Major subcellular locations involved in drug metabolism
ER through action of CYP450 enzymes, as well as other metabolic enzymes in the cytoplasm
Phase I metabolism
Addition of functional groups through oxidation/reduction/hydrolysis reactions, making the drug more polar and functionally altered
Phase II metabolism
Conjugation of the functional group on the drug to further inactivate and polarize the drug
Phase II reactions
Glycosylation
Sulfuric acid addition
Acetylation
Amination
Enzymes involved in oxidation reactions of phase I
Flavin-containing monooxygenases
Monoamine oxidase
Alcohol dehydrogenase
Aldehyde dehydrogenase
Enzymes involved in reduction reactions of phase I
NADPH-cytochrome P450 reductase
Alpha-ketoreductase
Phase II enzymes
UDP-glucuronosyltransferase Glutathione S-transferase Sulfotransferase N-acetyletransferase Methytransferase
Which phase II enzyme is the most important?
UDP-glucuronyltransferase
Major CYP450 enzymes associated with drug metabolism
CYP1A1
1A2
1B1
CYP2A6
2B6
2C8
2C9
2C19
2D6
2E1
CYP3A4
3A5What are the most important P450 enzymes?
CYP3A4/5: they account for >50% of the metabolism of clinically used drugs
What do all CYP450 enzymes need?
NADPH and oxygen, NADPH-CYP450 oxidoreductase
What kind of reactions do CYP450 enzymes carry out?
Hydroxylations Epoxidations N-S-oxidations O-/S-/N-dealkylations Deaminations Desulfurations Dechlorinations
How does grapefruit juice affect metabolism of certain drugs?
Inhibits CYP3A4, so it increases the half-life and decreases volume of distribution for a lot of drugs, potentially causing toxicity
Describe three principle factors known to influence drug metabolism
Age
Pregnancy
Race/ethnicity
