basic principles of drug metabolism

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1、BasicPrinciplesofDrugMetabolism2NAPLEXPg.51PhaseI(functionalization)Oxidation(mostimportant),reduction,andhydrolysisFunction:introduceapolargrouptomakemoleculesmorehydrophilicMethod:catalyzedbyhepaticCYP450systemenzymesGeneralPathwaysofDrugMetabolism-Functionistoattachsmall,polar,andionizablecompon

2、ents.Formwatersolubleconjugatedproducts.Conjugatedmetabolitesareeasilyexcretedintheurineandgenerallyhavelittleornopharmacologicactivityortoxicity.PhaseII(conjugation)phenytoinp-hydroxyphenytoinglucuronidehydroxylationglucuronidationconjugateofphenytoincefuroximeaxetilcefuroximehydrolysisaspirinsal

3、icylicacidglucuronidehydrolysis+glucuronidationaceticacidacetaminophenglucuronideandsulfateconjugatesconjugationExamplesofDrugMetabolismIntroductiontodruginteractionsTypesofdruginteractionReasonsforoccurrenceClinicalsignificanceDrugInteractionsGotoChapter17,pg.445AbsorptionInteractionsTetracycline-

4、divalentandtrivalentcationsCiprofloxacinantacidsDigoxin-cholestyramineThyroid-cholestyramineDigoxin-metoclopramideCiprofloxacin-sucralfateDistributionInteractionsWarfarin-aspirinWarfarin-chloralhydrateWarfarin-clofibrateWarfarin-ciprofloxacinMethotrexate-aspirinPg.451EnzymeInductionInteractions:Enz

5、ymeinducers:BarbituratesRifampinCigarettesmoking-alsocharredmeats/foodsPhenytoinPhenylbutazoneGriseofulvinCarbamazepineAlcohol(chronicingestion)MetabolicorBiotransformationInteractionsEnzymeinhibitors:Alcohol(acuteingestion)AmiodaroneCimetidineCo-trimoxazoleCyclosporineErythromycinMetronidazole–als

6、oother“azole”antifungalsReversetranscriptaseinhibitorsFluvoxamine/FluoxetineRitonavirExcretionInteractionsProbenecid-penicillins-naproxen-cephalosporinsLithium-diuretics-ACEinhibitors-Fluoxetine-NSAIDsPotassium-amiloride-triamterene-spironolactoneReviewlistofinteractionsonpg.452469.phenytoinp-hydr

7、oxyphenytoinglucuronidehydroxylationglucuronidationconjugateofphenytoincefuroximeaxetilcefuroximehydrolysisaspirinsalicylicacidglucuronidehydrolysis+glucuronidationaceticacidacetaminophenglucuronideandsulfa