Andersons pediatric cardiology 2107
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Priortoamoredetaileddiscussiononthepracticalapplicationsof
pharmacogeneticsandpharmacogenomicsincardiovascularpharmacotherapy,
knowledgeofthemajorbiotransformationalandtransportpathwaysisrequired.
Detailedhereinisabriefsummaryofthemostcommonenzymesandproteins
involvedinthedispositionofcardiovascular-relateddrugs(amore
comprehensivelistofothercontributingenzymesandproteinsissummarizedin
Tables79.1and79.2).Ifknown,informationonallelicvariationandontogenyis
included.
Table79.1
Drug-MetabolizingEnzymes
Enzyme/Gene Locationa
CYP1A2
Liver,colon
(rare)
Substratesb
Caffeine,propranolol,
verapamil,R-warfarin
CYP2B6
Liver,lung
Ketamine,methadone,
propofol
CYP2C8
CYP2C9
Liver
Liver,small
intestine
CYP2C19
Liver,small
intestine(rare)
CYP2D6
Liver,lung
(rare),brain
(rare),small
intestine(rare)
Cerivastatin,torsemide
NSAIDs:diclofenac,
ibuprofen,S-naproxen
ARBs:losartan,
irbesartan
Others:fluvastatin,
torsemide,S-warfarin
PPIs:esomeprazole,
lansoprazole,
omeprazole,
pantoprazole
Others:clopidogrel,
indomethacin,
labetalol,propranolol,
R-warfarin
Antiarrhythmics:
flecainide,mexiletine,
procainamide,
propafenone
β-blockers:atenolol,
carvedilol,metoprolol,
propranolol,timolol
Other:clonidine
Benzodiazepines:
alprazolam,
midazolam
Calciumchannel
blockers:amlodipine,
diltiazem,felodipine,
nifedipine,verapamil
CYP3A4/5/7
3A4:
Liver,
small
intestine,
lung(rare),
stomach
(rare),
Inhibitorsb
Cimetidine,dciprofloxacin,e
fluvoxaminee
Clopidogrel
Gemfibrozil,etrimethoprimf
Amiodarone,ffluconazole,e
fluvastatin
Cimetidine,esomeprazole,
lansoprazole,omeprazole,
pantoprazole
Inducersb
Omeprazole,
rifampin,tobacco
Phenobarbital,
phenytoin,
rifampin,
Rifampin
Rifampin
Rifampin
Amiodarone,dbupropion,e
cimetidine,dfluoxetine,e
paroxetine,equinidine,e
sertraline,fterbinafinef
Cimetidine,dclarithromycin,e
diltiazem,ferythromycin,f
fluconazole,fgrapefruit
juice,fketoconazole,e
indinavir,eitraconazole,e
ritonavir,gverapamilf
Barbiturates,
carbamazepine,
efavirenz,
nevirapine,
phenytoin,
rifampin,
ritonavir,gSt.
colon
(rare)
3A5:
Liver,lung
UGT1A1c
Liver
UGT1A3c
UGT2B7c
Liver
Liver
HMG-CoAreductase
inhibitors:
atorvastatin,lovastatin,
simvastatin
Immunosuppressives:
cyclosporine,
tacrolimus,sirolimus
Others:erythromycin,
midazolam,quinidine,
sildenafil,tadalafil
Bilirubin,carvediol,
Atazanavir,indinavir,
simvastatin
sorafenib
Atorvastatin
Gemfibrozil
Codeine,morphine,
lorazepam,propranolol
John'swort
aCYPlocationsummarizedfromZangerUM,SchwabM.CytochromeP450enzymesindrug
metabolism:regulationofgeneexpression,enzymeactivities,andimpactofgeneticvariation.
PharmacolTher.2013;138(1):103–141andPaineMF,HartHL,LudingtonSS,etal.Thehuman
intestinalcytochromeP450“pie”.DrugMetabDispos.2006;34(5):880–886.
bDatafrom />cUGTdatasummarizedfromdeWildtSN,KearnsGL,LeederJS,vandenAnkerJN.
Glucuronidationinhumans.Pharmacogeneticanddevelopmentalaspects.ClinPharmacokinet.
1999;36(6):439–452.
dWeakinhibitor.
eStronginhibitor.
fModerateinhibitor.
g
Canbebothaninhibitorandaninducer.
ARBs,Angiotensinreceptorblockers;NSAIDs,nonsteroidalantiinflammatorydrugs;PPIs,proton
pumpinhibitors.
Table79.2
DrugTransporters
Gene
Family
SLCO
Protein
Location
Substrates
Role
OATP1A2 Brain,kidney,
liver
OATP1B1 Liver
Indomethacin
CNSdistribution
OATP1B3 Liver
Digoxin,olmesartan,rosuvastatin,
telmisartan,valsartan
Digoxin,fluvastatin
OATP2B1 Liver,intestine,
placenta
Atorvastatin,bosentan,enalapril,
Hepaticuptake
pravastatin,rosuvastatin,simvastatin
acid
Hepaticuptake
Hepaticuptake,oralabsorption
SLC10A1 NTCP
Liver
SLC22
Kidney,brain
Kidney,brain
Kidney,placenta
Liver,brain,
smallintestine
Kidney,brain,
smallintestine
Heart,skeletal
muscle,liver,
adrenal
Kidney,liver
Kidney
Liver
OAT1
OAT3
OAT4
OCT1
OCT2
OCT3
SLC47
ABCB
MATE1
MATE2
BSEP
P-gp
(MDR1)
ABCC
MRP1
MRP2
MRP3
ABCG
MRP4
BCRP
Atorvastatin,fluvastatin,
pitavastatin,rosuvastatin
Acyclovir
Salicylates,valacyclovir
Hepaticuptake
Quinidine,verapamil
Renaluptake
Renaluptake
Renalsecretion
Hepaticandrenaluptake
Dopamine,norepinephrine
Renaluptake
Epinephrine,norepinephrine
Renalsecretion,biliaryexcretion
Renalsecretion
Lovastatin,pravastatin,rosuvastatin, Biliarysecretion
simvastatin
Cyclosporine,digoxin,
Oralabsorption,biliary
erythromycin,simvastatin
excretion,renalsecretion,CNS
distribution
Kidney,liver,
brain,small
intestine
Liver,small
intestine,kidney,
brain
Liver,kidney,
Pravastatin
smallintestine
Liver,kidney,
smallintestine
Liver,kidney
Liver,small
Pravastatin
intestine,
placenta
Biliaryexcretion,renalsecretion
Oralabsorption,biliaryexcretion
DatafromHoRH,KimRB.Transportersanddrugtherapy:implicationsfordrugdispositionand
disease.ClinPharmacolTherap.2005;78(3):260–277;NigamSK.Whatdodrugtransporters
reallydo?NatRevDrugDiscov.2015;14(1):29–44;KalliokoskiA,NiemiM.ImpactofOATP
transportersonpharmacokinetics.BritJPharmacol.2009;158(3):693–705.
