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40 Cards in this Set
- Front
- Back
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What 5 factors are know to affect drug metabolism?
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Inducers, inhibitors, genetics, Age, & health status
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What 5 factors are know to affect drug metabolism?
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Inducers, inhibitors, genetics, Age, & health status
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What is the most important enzyme in drug meta?
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Cytochrome P-450
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What is the critical 1st step leading to the elimin & termin of many drugs?
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Hydroxylation by CYP
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What are the charac of CYP?
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Over 50 in humans, 12 for xenobiotic meta, activites & rates vary
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How are CYP named?
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Root: CYP, Num: family, Letter: subfamily, Num: form
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What are the most active CYPs?
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CYP2C (8/9), CYP2D, CYP3A (4/5)
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What CYP is most abundantly expressed & involved in meta of ~50% clinically used drugs?
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CYP3A4
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Which CYPs are involved in endogenous oxidations?
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Higher #
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Which organs contain CYPs?
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Liver has most, GI, lung, kidney, CNS
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What is induction?
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When drugs inc the total amt & activity of some drg meta enzymes
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What enzymes can be induced?
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CYP, glucuronyl tranferase, epoxide hydrolase, & GSH transferase
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What are non-inducibile CYPs called?
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Constitutive
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What are the pharm effects of induction?
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Inc clearance, dec half life, dec pharm activity, possible inc/dec in toxic effect, hepatomegalia w/ phenobarbital
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What is an example of a drug that has inc toxic effects w/ induction?
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Acetaminophen
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What can induce CYP1A1/2?
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PAH, dioxin, benzopyrene (charbroiled beef), smoke, cruciferous veg (broccoli), omeprazole, food additives
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How do CYP1A1 & 2 differ?
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They are 69% identical but catalyze diff rxns. 1A1 is lower in human but 1A2 is a signif enzyme
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Describe the process in which dioxin induces CYP1A1/2.
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Binds high affinity receptor (Ah), enters nucleus, ass w/ ARNT, binds reg seq (xenobiotic reg/response elements, incmRNA, in CYP1A1/2 synthesis
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How is Ah expressed.
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Normally suppresssed by a protein so tha tlow levels are produced.
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What can induce CYP2B?
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Phenobarbital (barbituates)- induces CYP reductase by 20 fold & cytochrome b5, phenytoin, chlorpromazine, phenothiazine
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Decscribe the process in which phenobarbital induces CYP2B.
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Binds CAR (constit act receptor), dimeriz w/ RXR (retinoid x receptor), enters nucleus, binds PB elements on DNA, inc mRNA & protein
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What type receptor is CAR?
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Constitutively activated. When bound by androstanol or androstenol it's fcn is dec. Not high affinity
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What can induce CYP3A?
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PCN (pregnenolone-16-alpha-carbonitrile) & hyperforin (St Johns wart). Also steriods, HIV protease inhib (*ritonavir), *pacitaxel, carbamazepine, phenobarbital, phenytoin
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Decscribe the process in which CYP 3A is induced.
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Inducer binds PXR (Pregnane X Receptor), dimerizes w/ RXR, enters nucleus, binds response elements, induction
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What can induce CYP4A?
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Clofiric acid (antilipidemic), aspirin, nicotinic acid, dehydroepiandrosterone sulfate
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Describe the process in which CYP4A is induced.
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Binds PPAR-alpha (peroxisome prolif act receptor), dimerizes w/ RXR, cause prolif in hepatic peroxisomes
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What can induce CYP2E1?
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Ethanol, isoniazid (anti-tubercular), beta-hydroxybutyrate, acetone (diabetic ketosis)
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What CYP2E1 is responsible for the toxic metabolites of acetaminophen?
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CYP2E1
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Describe the process in which CYP2E1 is induced.
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No receptor involed. Stabilization of the protein->dec turnover->accumulation of CYP2E1
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What is competitive inhib?
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The inhibitor competes w/ substrate for the active site of the CYP->less substrate converted to product
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What is an example of a competitve inhibitor?
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Cimetidine (anti-ulcer) & Metyropone (anti-cortisol)
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What is noncompetitive inhibit?
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The inhibitoris metabolized to a reactive intermed that binds to the CYP enzyme & inactivates it; suicide activation or mech base activation
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Where is the site of rxn of the intermed in noncompet inhib?
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Heme
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What is a major inhib of CYP3A4?
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Grapefruit (6,7-dihydroxybergamottin) inhib in the small intestine. Also, erythromycin
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What drug is meta to a large extent in the gut by CYP3A4?
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Felodipine
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How does age affect drug meta?
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Newborns have undedeveloped capabilities, older rats have 30% less capabilities, [dec liver mass, hepaticblood flow, 1st pass, phase I rxns, changes in pharmacokinetics in elderly]
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What agent have dec hepatic clearance in elderly?
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antiarrhymics, anticonvulsants, antidepressants, antipsychotics, some beta blockers
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Describe the genetics of CYP,
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Extensive variation among pop, some individ are missing certain CYP (genetic polymorphism) [eg debisoquine & S-mephenytoin]
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Describe the genetics of N-acetyltransferase enzymes (NAT)?
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Bimodal distribution; some people fast & some are slow acetylators
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What are the 2 genetic polymorphisms of glucuronidation?
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Type 1 Crigler-Najjar syndrome (complete loss of bilirubin conjugating activity) & Gilbert's disease (doesn't abolish all the enzyme)
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