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27 Cards in this Set
- Front
- Back
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what is implied by the term elimination?
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drug metabolism - the original drug molecule has been chemically modified and is no longer present
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how does drug metabolism facilitate excretion?
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converts molecules to less lipophilic, more water soluble compounds that are less likely to be reabsorbed
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examples of drugs that are metabolized to toxic metabolites?
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acetominophen (toxic - acute liver failure) and benzo[a]pyrene (carcinogenic)
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definition of first-pass effect?
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extensive metabolism of a drug by the liver and/or intestine following oral administration of a drug
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areas primarily responsible for metabolism?
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portals of entry: liver, lung, skin, intestinal epithelium
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why is liver the most important metabolizing organ?
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size, cell type (highest concentration of enzymes), perfusion (25% of C), location (portal circulation)
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characteristics of phase I drug metabolism reactions?
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presynthetic reactions: add nothing greater than molecular weight 18 (water) to drug
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characteristics of phase II drug metabolism reactions?
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synthetic reactions: add higher molecular weight compounds (sugars, sulfate, etc) to drug
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which enzyme system is composed of NADPH cytochrome P450 reductase and cytochrome P450?
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microsomal mixed-function oxidase system
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what types of reactions are performed by the microsomal mixed-function oxidase system and what compounds do they utilize?
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hydroxylation reactions utilizing NADPH and molecular oxygen
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what is the most important component of the mixed-function oxidase system and why?
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cytochrome p450 because it is the site of drug substrate binding and oxygen activation
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why is cytochrome p450 an unusual enzyme?
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very broad substrate specificity therefore has the ability to metabolize many different compounds
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about how many different human p450s have been identified?
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58
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what is classification scheme for p450s?
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CYP[family, a numeral][subfamily, a letter][member, a numeral]
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some of the more important CYPs?
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CYP1A2, CYP2E1, CYP2D6, CYP3A4
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how is a CYP induced and what is the consequence?
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induction by drug or chemical due to enhanced transcription and is specific for 1 or 2 p450s; leads to enhanced rate of metabolism or inducing agent or a second drug
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what are two things to note about induction?
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requires a finite amount of time and can be reversed when the inducing agent is withdrawn
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how can one drug inhibit CYP metabolism of a second drug?
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when both are metabolized by the same CYP
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what is true of drugs that induce CYP?
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many also induce glucuronosyl transferase
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what makes glucuronide very hydrophilic?
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derived from a sugar (higher water solubility) and contains a carboxyl group that is ionized at physiological pH
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what drugs induce sulfotransferases?
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non inducible
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enzyme responsible for catalyzing addition of glutathione to electrophilic substrates?
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glutathione S-transferase
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what are the amino acids in GSH and which one is reactive?
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glutamic acid, cysteine, glycine; cysteine is the reactive amino acid
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what are final steps give the product for glutathione S-transferase reactions?
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glutamic acid and glycine are cleaved and the amino group of cysteine is acetylated prior to excretion therefore giving a N-acetylcysteine derivative
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how are p450 genes inherited?
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autosomal recessive
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acute and chronic metabolic consequences of alcohol?
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acute: inhibit drug metabolism; chronic: induce CYP2E1 (make acetaminophen more hepatotoxic); excessive: cirrhosis and decreased metabolism
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what can affect relationship of drug metabolism to drug therapy?
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genetic, environmental, disease, and age
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