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1、ReviewJPP2009,61:541–558ß2009TheAuthorsCytochromeP450-mediatedmetabolismReceivedOctober14,2008AcceptedDecember12,2008inthehumangutwallDOI10.1211/jpp/61.05.0002ISSN0022-3573KirstinThelenandJenniferB.DressmanInstituteofPharmaceuticalTechnology,GoetheUniversity,FrankfurtamMain,GermanyAbstractObjec
2、tiveAlthoughthehumansmallintestineservesprimarilyasanabsorptiveorganfornutrientsandwater,italsohastheabilitytometabolisedrugs.Interestinthesmallintestineasadrug-metabolisingorganhasbeenincreasingsincetherealisationthatitisprobablythemostimportantextrahepaticsiteofdrugbiotransformation.Keyfindin
3、gsAmongthemetabolisingenzymespresentinthesmallintestinalmucosa,thecytochromesP450(CYPs)areofparticularimportance,beingresponsibleforthemajorityofphaseIdrugmetabolismreactions.ManydruginteractionsinvolvinginductionorinhibitionofCYPenzymes,inparticularCYP3A,havebeenproposedtooccursubstantiallyatt
4、heleveloftheintestineratherthanexclusivelywithintheliver,asoriginallythought.CYP3AandCYP2CrepresentthemajorintestinalCYPs,accountingforapproximately80%and18%,respectively,oftotalimmunoquantifiedCYPs.CYP2J2isalsoconsistentlyexpressedinthehumangutwall.InthecaseofCYP1A1,largeinterindividualvariati
5、onintheexpressionlevelshasbeenreported.DatafortheintestinalexpressionofthepolymorphicCYP2D6areconflicting.SeveralotherCYPs,includingthecommonhepaticisoformCYP2E1,areexpressedinthehumansmallintestinetoonlyaverylowextent,ifatall.ThedistributionofmostCYPenzymesisnotuniformalongthehumangastrointest
6、inaltract,beinggenerallyhigherintheproximalregionsofthesmallintestine.SummaryThisarticlereviewsthecurrentstateofknowledgeofCYPenzymeexpressioninhumansmallintestine,theroleofthegutwallinCYP-mediatedmetabolism,andhowthismetabolismlimitsthebioavailabilityoforallyadministereddrugs.Possibleinteracti
7、onsbetweendrugsandCYPactivityinthesmallintestinearealsodiscussed.KeywordscytochromeP450;CYP;first-passmetabolism;gutwallmetabolism;intestinalmetabolismIntroductionAlthougharolefortheintestineinthemetabolismofdrugshasbeenrecognised
