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Drug metabolizing enzyme activities versus genetic variances for drug of clinical pharmacogenomic relevance.doc

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Drug metabolizing enzyme activities versus genetic variances for drug of clinical pharmacogenomic relevance

WuClinicalProteomics2011,8:12 /content/8/1/12 CLINICAL PROTEOMICS REVIEW OpenAccess Drugmetabolizingenzymeactivitiesversus geneticvariancesfordrugofclinical pharmacogenomicrelevance AlanHBWu Correspondence:wualan@labmed2. Abstract DepartmentofLaboratory Enzymesarecriticallyimportantinthetransportation,metabolism,andclearanceof mosttherapeuticdrugsusedinclinicalpracticetoday.Manyoftheseenzymeshave significantgeneticpolymorphismsthataffecttheenzyme’sratekinetics.Regarding drugmetabolism,specificpolymorphismstothecytochrome(CYP)P450enzyme familyarelinkedtophenotypesthatdescribereactionratesas“ultra”,“intermediate”, and“poor,”asreferencedto“extensive”metabolizersthatareassignedtowildtype individuals.Activityscoresisanalternatedesignationthatprovidesmoregenotype- to-phenotyperesolution.Understandingtherelativechangeinenzymeactivitiesor rateofclearanceofspecificdrugsrelativetoanindividual’sgenotypesisan importantcomponentintheinterpretationofpharmacogenomicdatafor personalizedmedicine.Currently,themostrelevantdrugmetabolizingenzymesare CYP2D6,CYP2C9,CYP2C19,thiopurinemethyltransferase(TPMT)andUDP- glucuronosyltransferase(UGT).Eachoftheseenzymesisreactivetoahostof differentdrugsubstrates.Pharmacogenomicteststhatareinroutineclinicalpractice includeCYP2C19forclopidogrel,TPMTforthiopurinedrugs,andUDP-1A1for irinotecan.Othertestswherethereisconsiderabledatabuthavenotbeenwidely implementedincludesCYP2C9forwarfarin,CYP2D6fortamoxifenandcodeine,and CYP2C19fortheprotonpumpinhibitors. Medicine,UniversityofCalifornia, SanFrancisco,SanFrancisco GeneralHospital,1001Potrero,San FranciscoCA94110,USA 1.Introduction Pharmacogenomics isanimportant toolforthepersonalization ofmedicaltherapeu- tics.Thedeterminationofanindividual’sgenotypeforkeyenzymesthatparticipatein thetransportation, metabolism, and clearance is astrong determinant oftherapeutic efficacy andtoxicity avoidance. Regardingdrugmetabolism, subjects whohavenoor slowerrateofenzymeactivitythannormalhavehighercirculationdrugco