Andersons pediatric cardiology 2108
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DrugBiotransformation
Themajorityofdrugbiotransformationoccursintheliver.Extrahepatictissues
docontaindrug-metabolizingenzymes,althoughtheirrelativecontributionsto
overallbiotransformationaretypicallynotaspronouncedasthoseoftheliver.
DrugbiotransformationreactionsarecategorizedintophaseI(e.g.,CYPmediatedoxidation)andphaseII(e.g.,UGT-mediatedglucuronidation).The
relativecontributionofCYPenzymestodrugmetabolismissummarizedinFig.
79.3.Theontogenyofdrugmetabolismenzymes,summarizedbyHines,1is
characterizedtoalargerextentcomparedwithdrugtransportersandisessential
indeterminingthepotentialgenotype-phenotyperelationshipfortheindividual
child.
FIG.79.3 RelativecontributionofcytochromePs(CYPs)todrug
metabolism.TheestimatedcontributionsofindividualhumanCYPstothe
metabolismofclinicaldrugs.(ModifiedfromZangerUM,SchwabM.
CytochromeP450enzymesindrugmetabolism:regulationofgene
expression,enzymeactivities,andimpactofgeneticvariation.Pharmacol
Ther.2013;138[1]:103–141.)
CYP2D6
CYP2D6isanimportantphase1drugmetabolizingenzyme(DME)that
contributestothemetabolismofapproximately20%to25%ofdrugsused
clinically,9,10despitecomprisingonly2%to5%ofthetotalhepaticCYP
content.11,12Expressionisundetectableinthefetusbutrapidlyincreases
postnatallytonearadultlevelswithinthefirstfewweeks.1CYP2D6isthe
predominantpathwayforbioactivationoreliminationofmanycardiovascular
medications,includingantiarrhythmicsandβ-blockers.13Thehighly
polymorphicCYP2D6generesidesonchromosome22q13.1,locatedcloseto
twononfunctionalgenes,CYP2D7andCYP2D8.14,15Currentlyover100allelic
variantshavebeenidentified(withan
extensiverangeofabsent,decreased,normal,orexcessiveallelicfunctions
resultinginvariableinterindividualCYP2D6enzymeactivity.16Giventhearray
ofpossibleallelicfunctionality,itisnotsurprisingthathepaticCYP2D6protein
expressionvariesdramaticallyamongindividuals.17Additionally,this
expressioncanbehighlyvariablewithintheworld'spopulationandvarious
ethnicgroups.18
Thepoormetabolizerphenotype,comprisingindividualscarryingno
functionalalleles(i.e.,*3,*4,*5,*6),andtheultrarapidmetabolizerphenotype,
compromisingindividualscarryinganincreaseoffunctionalalleleswitha
normallyfunctionalallele,representthebroadrangeofpossibleenzymeactivity.
Ahigherriskofadverseeventsortreatmentfailurecanoccurinthese
phenotypicgroupsbasedonthedruginvolved.Forinstance,mostantiarrhythmic
drugsaremetabolicallydeactivatedbyCYP2D6,thusplacingpoormetabolizers
athigherriskfordrugaccumulation,leadingtoadverseeventsortoxicity.
Conversely,inthesameexample,ultrarapidmetabolizerphenotypeswouldbeat
riskforextensivemetabolismandclearanceoftheactivedrug,potentially
leadingtodecreasedefficacy.Thisexampleiscontrastedwithcodeine,where
CYP2D6metabolicallyactivatesthedrugtoproducemorphine.Inthisscenario,
thepoormetabolizerphenotypeissusceptibletotreatmentfailureordecreased
efficacysecondarytodecreasedmorphineproduction.Conversely,theultrarapid
metabolizerphenotypeisatriskforopioidtoxicityduetoincreasedplasma
concentrationofmorphinefromenhancedCYP2D6-mediatedproduction.
CYP2C9
CYP2C9,comprisinganaverageof20%ofthetotalhepaticCYPcontent,12
contributestothemetabolismofapproximately12%to13%ofclinicallyused
drugs.19–21ExpressionofCYP2C9isminimalduringearlyfetallife,increasing
tolevels10%ofadultvaluesinthethirdtrimester.1Afterbirthto5monthsof
age,proteinexpressionofCYP2C9isabout25%ofadultlevels.22Ofconcern,
thisagegroupdisplayedthehighestdegreeofinterindividualvariabilityof
CYP2C9expression,with50%oftheinfantshavingnochangeinexpression
comparedwiththird-trimesterfetallivers;conversely,othersdemonstrate
expressionnearlyequivalenttoadultlevels.Collectively,thistranslatestoa
nearly35-foldrangeinenzymeexpressionoverthefirst5monthsoflife.Less
variabilityisobservedfrom5monthsto18years,whereCYP2C9levelswere
approximately50%ofadultvalues.However,anabsenceofadultlevels
observedinsomepostpubertalsamplesbyTreluyeretal.suggeststhatthe
maturationofCYP2C9couldoccurlaterinchildhood.23Thisdeterminationof
lateCYP2C9isnotconsistentwithinvivopharmacokineticdatainchildren,
wheremetabolismofCYP2C9substrateswascomparabletoadults.1Clearly
thesediscrepancieswarrantfurtherinvestigation,buttheylikelyresultfrom
pharmacogeneticandphysiologicchangesinlivermass,assummarizedfurther
onwithwarfarinmetabolism.24
MostoftheexpressionandmetabolicactivityofCYP2C9occursintheliver;
however,CYP2C9isquantitativelythesecondmostcommonisoform(~15%)
foundinthehumanintestinefollowingtheCYP3Asubfamily(~80%).25Despite
thehumanintestinalcontentbeingofanorderofmagnitudelessthanthatofthe
liver,12thelargedegreeofvariabilityofintestinalCYP2C9contentandactivity
amongindividualscouldresultinvariabledrugexposuresecondarytodecreased
presystemicclearanceofCYP2C9substrates(e.g.,fluvastatin,warfarin).
Collectively,thereisapaucityofdataregardingtheroleofintestinalCYPsand
theirrespectivecontributionstodrugexposure,andnothingrelatedtothe
ontogenyofCYP2C9inextrahepatictissueisknown.Forthepurposeof
precisiontherapeutics,theroleofextrahepaticCYP2C9andCYP3Ashouldbe
consideredinthedesignofpharmacogeneticandpharamacogenomictrialsand
clinicaldecisionmaking.
CYP2C9,locatedonchromosome10q23.33,exhibitsgeneticpolymorphism
withover60allelicvariantscurrentlyreported
(AsopposedtoCYP2D6,most
CYP2C9allelicvariantsresultonlyinadecreaseoffunction.Infact,CYP2C9*2
