Involvement of Cytochromes P450 in Drug-Drug Interactions ...

1 CONTINUINGMEDICALEDUCATIONI nvolvementofCytochromesP450inDrug-DrugIn teractions:AnOverviewC EOng,PhD*,L KTeh,PhD**,RIsmail,PharmD**"'Departmento fPharmacy,InternationalMedicalUniversity ,SesamaCentre-PlazaKomanwel,BukitJalil,5 7000 KualaLumpur,**DepartmentofPharmacy,Facul tyofMedicine,UniversitiMalaya,50603 KualaLumpur;**DepartmentofPharmacology,S choolofMedicalSciences,UniversitiSainsMa laysia,16150 KotaBharu, (suchasfood,chemicals,ordrugs) ( ),pharmacokinetic,orpharmacodynamicbasis 1 Themostcommonmechanismforclinicallyimpor tantdrug-druginteractionsispharmacokinet icinteraction2,3, ( ,distribution,Thisarticlewasaccepted:4 February2002 CorrespondingAuthor:OngChinEng,Departmen tofPharmacy,InternationalMedicalUniversi ty,SesamaCentre-PlazaKomanwel,BukitJalil ,57000 KualaLumpurMedJ MalaysiaVol57No2 June2002251 CONTINUINGMEDICALEDUCATION metabolismandexcretion)ofa ,alteringtheamountofdrugabsorption( );displacementfromproteinbindingsites,in creasingthefree,activeconcentrationofone orboththedrugs.

2 Andmostimportantly, , ,drugmetabolismoccursmainlyintheliver,al thoughthegut,kidneys,lungs, ,drugmetabolismoccursintwophases,PhaseI (oxidation)andPhaseII(glucuronidation) ,viathecytochromeP450mixed-functionoxida sesystem,aPhaseI processThelargestquantitiesofcytochromeP 450(CYP)enzymesarelocatedintheliver,alth oughtheyarealsofoundinthegut,kidneys,lun gs, , ,CYP2,andCYP3,specificallyinvolvingtheCY P1A2,CYP2C9,CYP2C19,CYP2D6, ,theirrespectiveinducers, , , , ( ,11providedanexplanationforseveralcasere portsintheearly1990sdescribingserioussid eeffects, , (whereasthemetabolitesdonot).Thisleadsto anincreasedMedJ MalaysiaVol57No2 June2002 InvolvementofCytochromesP450inDrug- ,therefore,providesaclassicexampleindica tingthecriticalimportanceofdrugmetabolis manddruginteractioninthedevelopment,regu lation, ,itraconazole, , ,a serotoninagonistusedintreatmentofgastroe sophagealreflux,followingitsadministrati onwithCYP3A4inhibitors,havealsobeenassoc iatedwithQTprolongationandtorsadesdepoin tes, , (SSRls) 's(Prozac ,EliLillyCompany,Indianapolis,USA)launch in1988, ,paroxetine,fluvoxamine, ,particularlytheirminimalquinidine-likep roperties,lowornoMedJ MalaysiaVol57No2 June2002anticholinergiceffects, , ,assuch, ,theycaninhibitCYP2D6tosomeextent, , (TCA) , , ,constipation,tachycardia,hypotension,ar rhythmia, ,18.)

3 Fluoxetine>sertraline> :paroxetine::::fluoxetine::::norfluoxeti ne>sertraline>fluvoxamine> , ,paroxetineandfluoxetineprovemorepotentt hansertraline,fluvoxamine,andcitalopram2 2, ,includingtheophylline'4,haloperidoF5,cl ozapine26, ,theobservationofincreasedserumconcentra tionsofdrugsmetabolisedbyCYPZC isozymes,suchasphenytoin,tolbutamide,and diazepam, , ,29, ,itisprudenttosuspectanySSRI ashavingapotentialinteractionatagiveniso zyme, , (asubstrateofCYPZD6) ,theroutineprescriptionofSSRI sinbothchildrenandadults, , ,mostuntowardeffectsowingtoSSRI drug -druginteractionsaremildsymptomsrela tedtoincreasedserumconcentrationofmedica tionsusedincombinationwithSSRIs,Therefor e, , ( ,sulfonamides)andantifungals(e, ,fluconazole),alongwithadditionaldrugsfo rotherAIDS-relatedconditions,Thismultidr ugregimenincreasesthechanceofdruginterac tionsinAIDS patients31,Numerousinvitrostudieshavesho wnthatthefirst-generationproteaseinhibit orsare excellentsubstratesforCYP3A4, ,therelativelypoororalavailabilityofHIVp roteaseinhibitors(saquinavir<indinavir<n elfinavir<ritonavir) ,enzymeinducerssuchasrifampinmarkedlydec reasedtheinhibitors'plasmalevels( ,indinavir,andnelfinavir,and35%forritona vir).

4 Accordingly,therapeuticconcentrationsare notlikelytobeachieved,andMedJ MalaysiaVol57No2 June2002 InvolvementofCytochromesP450inDrug- ~larithromycin,havebeenobservedtomodestl ymcreasetheplasmalevelsofritonavirindina virandnelfinavir,butgenerallynots~fficie ntt~ ,theinteractionofketoconazoleandsaquinav irwasfoundtobemorepronounced, ;forexample,theplasmalevelsofrifabutinan ditsactivemetaboliteincreasedtwo-tosixfo ldwheneitherritonavir,indinavir, ,theconcurrentuseofHIVproteaseinhibitors withCYP3 Asubstratesthathavenarrowtherapeuticindi cesorthosetendtocauseserioussideeffects( ,astemizole,cisaprideandmidazolam) ,however, agentsbytwo-toeightfold,andinthecaseofri tonavir,thisresultsina strategytoimprovetheactivityofsaquinavir , ,asreductionofdosagerequirementforsaquin avirwillminimizeMedJ MalaysiaVol57No2 ,toavoid?

5 Otentialdangerous(oradverse) drug -drugmte ractions, ,druginteractionscausedbymutualinhibitio narealmostinevitable, ,however,beemphasisedthatonlyafewdrugint eractions, ~ofametabolicdruginteractionwilldependon themagnitudeofthechangeintheconcentratio nofactivespecies(parentdrugormetabolites ) , 'warningbox'indrugmanufacturer' "laundry"listofsignificantdruginteractio nsinstandardmedicalreferencessuchasPhysi cian' , , :HaddadLM(ed).ClinicalManagementofPoison ingandDrugOverdose(3rded).Philadelphia:W ESaunders, , ;57 ;43 ;22 ,CrawfordK,CyrT, ;22 , ;43 , ;43 ;13 ;21(3) , ;35 , ;38 ,LeesonGA,BurmasterSDHookRHReithMK, 'terfenadin~associatedwithCYF3A(4) ;23 ,ChenY,FreimanJP, ;269 ,NeuvonenPJ, ;27 ;36 Cardiol1993;72 ,GohYD,AddisonRS, ;65 Psychiatry1988;145 , Psychiatry1993;150 ,AntonRF, Psychiatry1993;150 ,AldermanJ, ;14 ,BaldessariniRJ, ;51 ,WatermanGS,RyanNet AmerAcadChildAdolescPsychiatry1994;33 :potentialdrug- ;16(suppl2) ;6 ,RandolphC, ;14 ,WeigmannH, ;14 MalaysiaVol57No2 June2002 InvolvementofCytochromesP450inDrug- ,PollicinoAM, ;15 ]ClinPsychiatry1992;53 Csuppl) ,DeVaneCL, ]Psychiatry1996;153 , :Review.

6 ]ClinPsychopharmacol1997;17 ,GibbonsS,BackD, ;32 ,FrommMF,WandelC, ] ClinInvest1997;101 ],MarshKC, ;41 (s)ModelinducerCYP1A2caffeinefurafylline polycyclichhenacetinfluvoxaminearomatice terocyclichydrocarbonsarylaminestheophyl lineCYP2C9tolbutamidesulphaphenazolephen obarbitalS-warfarinphenretoindicloenacCY P2C19S-mephenytoinS-mephenytoinomeprazol ediazepamCYP2D6debrisoquinequinidinenon- induciblesparteinemetoprololcodeinetricy clicantidepressantsCYP3A4nifedipineketoc onazoledexamethasonemidazolamtestosteron ecyclosporinAterfenadineerythromycincarb amazepine258 MedJ MalaysiaVol57No2 June2002 InvolvementofCytochromesP450inDrug-DrugI nteractions:AnOverviewTableIIInhibitiono fcytochromesP450byselectiveserotoninreup takeinhibitorsSSRIF luoxetineSertralineParoxetineFluvoxamine CYPisozymesinhibitedaCYP2D6+++CYP2C++CYP 3A4+CYP2D6+CYP2C+CYP3A4+CYP2D6+++CYP1A2+ ++CYP2C++CYP3A4++Potentialdruginteractio nsbsecondaryaminetricyclicantidepressant s,haloperidol,type1 Cantiarrhythmicsphenytoin,diazepamcarbam azepine,alprazolam,terfenadinesecondarya minetricyclicantidepressants,antipsychot ics,type1 Cantiarrhythmicstolbutamide,diazepamcarb amazepinesecondaryaminetricyclicantidepr essants,antipsychotics,type1 Cantiarrhythmics,trazodonetheophylline,c 1ozapine,haloperidol,amitriptyline,imipr aminediazepamcarbamazepine,alprazolam.

7 TerfenadineadegreeofinhibitionofSSRI oneachisozymeisrepresentedasfollows:+++s ubstantial,++moderate,and+ MalaysiaVol57No2 ProteaseinhibitorsarealsosubstratestoP-g lycoprotein260 MedJMalaysiaVol57No2 June2002