Edited by

Pavel Anzenbacher and

Ulrich M. Zanger

Metabolism of Drugs and Other Xenobiotics

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Edited by Pavel Anzenbacher and Ulrich M. Zanger

Metabolism of Drugs and Other Xenobiotics

The Editors

Prof. Pavel AnzenbacherPalacky University at OlomoucDept. PharmacologyHnevotinska str. 3779 00 OlomoucCzech Republic

Prof. Dr. Ulrich M. ZangerDr. Margarete Fischer-Bosch Institute of Clinical PharmacologyAuerbachstr. 11270376 StuttgartGermany

CoverNabumetone bound in the active site of cytochrome P450 1A2 (Anzenbacherova, Berka et al., 17th Intl. Conference Cytochromes P450, Manchester 2011).

The structure has been supplied by Dr. Karel Berka.

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Print ISBN: 978-3-527-32903-8ePDF ISBN: 978-3-527-63091-2ePub ISBN: 978-3-527-64632-6mobi ISBN: 978-3-527-64633-3oBook ISBN: 978-3-527-63090-5

Cover Design Adam-Design, WeinheimTypesetting Toppan Best-set Premedia Limited, Hong KongPrinting and Binding Markono Print Media Pte Ltd, Singapore

V

Contents

Preface XXIII ListofContributors XXV

PartOne BiochemistryandMolecularGeneticsofDrugMetabolism 1

1 Drug-MetabolizingEnzymes–AnOverview 3 PavelAnzenbacherandEvaAnzenbacherová1.1 Introduction:FateofaDrugintheHumanBody 31.2 ClassificationSystemsofDrug-MetabolizingEnzymesAccordingto

DifferentCriteria 41.3 OverviewoftheMostImportantDrug-MetabolizingEnzymes 61.3.1 CYPs 61.3.2 Peroxidases 81.3.3 FlavinMonooxygenases 101.3.4 OtherOxidases:AmineOxidases,andMolybdenum-ContainingXO

andAO 111.3.5 NADPHOxidase,NAD(P)HOxidoreductase,andDihydropyridine

Dehydrogenase 131.3.6 Reductases 141.3.7 ConjugatingEnzymes 15 Acknowledgments 20 References 20

2 CytochromesP450 27 F.PeterGuengerich2.1 IntroductionandHistoricalPerspective 272.2 NomenclatureandGeneOrganization 292.3 Regulation 322.3.1 TranscriptionalRegulation 322.3.2 Post-TranslationalandEpigeneticRegulation 342.3.3 Post-TranslationalRegulation 34

VI Contents

2.4 Polymorphisms 352.5 ProteinStructure 372.6 CatalyticMechanisms 402.7 WhatDeterminesP450CatalyticSelectivity? 452.8 OxidativeStressandP450s 472.9 RelevanceinDrugMetabolismandClinicalMedicine 48 References 53

3 UDP-Glucuronosyltransferases 67 ChristianP.StrassburgandSandraKalthoff3.1 Introduction 673.2 ASimplePhenotype:UnconjugatedNonhemolytic

HyperbilirubinemiaandGlucuronidation 673.3 OrganizationofUGTsandtheUGT1AGeneLocus 683.4 UGT1AGeneNomenclature 703.5 HumanUGT1AGeneLocusandSequenceVariability 713.6 GlucuronidationofBilirubin 783.7 UGT1A1Gene 793.8 IsThereanAdvantageorRiskAssociatedwithUGT1A1

Variability? 803.9 UGT1A1GeneandPharmacogeneticProtection 823.9.1 CardiovascularDisease 823.9.2 Cancer 823.10 UGT1A1GeneandPharmacogeneticRisks 833.10.1 DispositiontoDrugToxicity 833.10.1.1 IrinotecanToxicity 833.10.1.2 JaundiceinProteaseInhibitorTherapy(Atazanavirand

Indinavir) 863.11 UGT1A1VariabilityandCancerRisk 863.11.1 CRC 873.11.2 BreastCancer 873.12 UGT1A3Gene 873.13 UGT1A7Gene 883.13.1 CRC 933.13.2 HCC 933.13.3 PancreaticCancer 943.14 TranscriptionalRegulationofUGT1AGenes 953.15 ArylHydrocarbonReceptor/ArylHydrocarbonReceptorNuclear

TranslocatorRegulationofUGT1AGenes 953.16 RegulationbyHepaticNuclearFactors 973.17 RegulationbytheFarnesoidXReceptor 973.18 RegulationbyNuclearFactorErythroid2-RelatedFactor2 983.19 RegulationbySpliceVariants 983.20 AnimalModelstoStudyUGT1AGenes 993.21 Outlook 100

Contents VII

Acknowledgments 101 References 101

4 Sulfotransferases 117 MichaelW.H.Coughtrie4.1 Introduction 1174.2 Background 1184.3 PAPSSynthesis 1194.4 SULTEnzymeFamily 1214.4.1 SULT1Family 1214.4.2 SULT2Family 1264.4.3 SULT3,4,5and6Families 1274.5 AssaysforSULTActivity 1284.6 StructureandFunctionofSULT 1284.7 SULTPharmacogenetics 1324.8 BioactivationandtheRoleofSULTsinToxicology 1334.9 ConclusionsandFuturePerspectives 135 References 135

5 GlutathioneS-Transferases 147 MiroslavDostalekandAnna-KatarinaStark5.1 IntroductionandHistory 1475.2 Nomenclature,Structure,andFunction 1485.2.1 CytosolicGSTs 1485.2.1.1 GSTA,GSTM,andGSTPClasses 1495.2.1.2 GSTSClass 1495.2.1.3 GSTTClass 1495.2.1.4 GSTOClass 1505.2.1.5 GSTZClass 1505.2.2 MitochondrialGSTs 1505.2.3 MicrosomalGSTs 1505.3 Substrates 1515.4 Regulation,Induction,andInhibition 1515.5 GenePolymorphismofGSTs 1555.5.1 GSTAPolymorphism 1565.5.2 GSTMPolymorphism 1565.5.3 GSTTPolymorphism 1565.5.4 GSTP1Polymorphism 1575.5.5 GSTOPolymorphism 157 References 157

6 HydrolyticEnzymes 165 BingfangYan6.1 Carboxylesterases 1656.1.1 Overview 165

VIII Contents

6.1.2 ClassificationandStructuralFeatures 1666.1.2.1 HumanCarboxylesterases 1666.1.2.2 SalientFeaturesofCarboxylesterases 1676.1.2.3 SecondaryandCrystalStructure 1676.1.3 CatalyticMechanism,SubstrateSpecificity,andActivatorsand

Inhibitors 1686.1.3.1 CatalyticMechanism 1686.1.3.2 SubstrateSpecificity 1696.1.3.3 ActivatorsandInhibitors 1706.1.4 PharmacogenomicsofCarboxylesterases 1726.1.4.1 Polymorphisms 1736.1.4.2 InteractionwiththeCytochromeP450EnzymeSystem 1736.1.4.3 InteractionwithUDP-Glucuronosyltransferases 1746.1.4.4 InteractionswithDrugTransporters 1756.1.4.5 Drug–InsecticideInteractions 1756.1.5 ComparisonbetweenHumanandAnimalCarboxylesterases 1756.1.5.1 TissueDistribution 1766.1.5.2 Species-SpecificHydrolysis 1766.1.5.3 OntogenicExpression 1776.1.5.4 RegulatedExpression 1776.2 EpoxideHydrolases 1786.2.1 Overview 1786.2.2 ClassificationandStructuralFeatures 1796.2.3 CatalyticMechanisms 1806.2.4 ComparisonamongVariousEHs 1816.3 Paraoxonases 1836.3.1 Overview 1836.3.2 ClassificationandStructuralFeatures 1846.3.3 CatalyticMechanism 1856.4 OtherHydrolases 1886.4.1 CarbonicAnhydrases 1886.4.2 Cholinesterases 1886.4.3 β-Glucuronidase 1896.4.4 Lipases 1906.4.5 Peptidases/Proteases 1906.4.6 Valacylovirase 190 References 191

7 TransportingSystems 199 AnneT.Nies,ClaudiaResch,andTadashiNamisaki7.1 Introduction 1997.2 ClassificationofDrugTransportersandTransport

Mechanisms 1997.3 DrugTransportersoftheSLCSuperfamily 2007.4 ABCDrugTransporters 208

Contents IX

7.5 DrugTransportersandDisease 2087.6 DrugTransportersandPharmacokinetics 2127.6.1 IntestinalTransporters 2127.6.2 HepaticTransporters 2137.6.3 RenalTransporters 2137.6.4 TransportersattheBlood–BrainBarrier 2147.7 RoleofDrugTransportersinChemotherapyResistance 2147.8 PharmacogenomicsofDrugTransporters:ImplicationsforClinical

DrugResponse 215 Acknowledgments 215 References 216

8 TranscriptionalRegulationofHumanDrug-MetabolizingCytochromeP450Enzymes 223

ZdenekDvorak8.1 FactorsAffectingDrug-MetabolizingCytochromesP450 2238.1.1 GeneticPolymorphism 2238.1.2 PhysiologicalandPathophysiologicalFactors 2248.1.3 EnvironmentalFactors 2248.2 TranscriptionalRegulationofCYP 2248.2.1 Xenoreceptors,andSteroidandNuclearReceptors 2258.2.1.1 ArylHydrocarbonReceptor 2258.2.1.2 PregnaneXReceptor 2268.2.1.3 ConstitutiveAndrostaneReceptor 2268.2.1.4 SteroidandNuclearReceptors 2278.2.2 TranscriptionalMechanisms 2278.2.2.1 DirectBindingtotheGenePromoter 2278.2.2.2 IndirectBindingtotheGenePromoter 2278.2.2.3 RegulatingtheRegulator 2288.2.3 ReceptorCross-Talk 2288.2.3.1 LigandSharing 2288.2.3.2 ResponseElementSharing 2288.2.3.3 ReceptorCascade 2288.2.3.4 CoactivatorSharing 2298.2.3.5 MetabolicCross-Talk 2298.2.4 Ligands–AgonistsandAntagonists 2298.3 RegulationofDrug-MetabolizingCYPs 2308.3.1 CYP1ASubfamily 2308.3.2 CYP1B1 2328.3.3 CYP2A6 2338.3.4 CYP2B6 2348.3.5 CYP2CSubfamily 2358.3.6 CYP3ASubfamily 236 Acknowledgments 238 References 238

X Contents

9 ImportanceofPharmacogenomics 259 UlrichM.Zanger,KathrinKlein,andJessicaRieger9.1 Introduction 2599.2 PharmacogeneticPolymorphisms 2609.2.1 LessonsfromEarlyExamples 2609.2.2 CytochromeP450Polymorphisms 2639.2.3 PolymorphismsinFurtherDrug-MetabolizingEnzymes 2689.2.4 PolymorphicDrugTransporters 2699.3 PolygenicandMultifactorialAspectsofDrugMetabolism

Phenotype 2709.3.1 PolygenicInheritance:CYP1A2andCYP3A4Conundrums 2709.3.2 EpigeneticInfluencesonDrugMetabolism 2729.4 GenomicsTechnologiesandApproaches 2739.4.1 GWAS–AMaturedToolinPharmacogenomics 2749.4.2 GeneticalGenomics:IdentifyingNovelPolymorphicADMEGenes 2759.5 Conclusions 276 References 276

PartTwo MetabolismofDrugs 285

10 IntroductiontoDrugMetabolism 287 UlrichM.Zanger10.1 Introduction 28710.2 HistoricalAspects 28710.3 DiversityofDrugMetabolicPathways 28810.4 InfluenceofDrugMetabolismonPharmacologicalActivity 28910.5 Biotoxification 29010.6 ExtrahepaticDrugMetabolism 29010.7 FactorsAffectingDrugMetabolismActivity 29110.7.1 GeneticPolymorphism 29110.7.2 Sex 29210.7.3 Age 29310.7.4 InfluenceofDiseasesandPathophysiologicalFactors 29410.7.5 EnvironmentalInfluences 29410.8 Conclusions 296 References 296

11 CentralNervousSystemDrugs 301 PierreBaumannandChristophHiemke11.1 Introduction 30111.2 Antidepressants 30111.2.1 TricyclicAntidepressantsandStructurallyRelated

Compounds 30211.2.2 SSRIs 30311.2.3 OtherRecentAntidepressants 305

Contents XI

11.2.4 MAOInhibitors 30611.3 Antipsychotics 30611.3.1 PhenothiazinesandThioxanthenes 30611.3.2 ButyrophenonesandRelatedCompounds 30711.3.3 AtypicalAntipsychotics 30711.4 TranquillizersandHypnoticAgents 30911.5 Psychostimulants 31111.6 AnticonvulsantsandMoodStabilizers 31111.7 AgentsforDementiaandCognitiveEnhancers 31311.8 AntimigraineDrugs 31311.9 OtherDrugs 31411.10 Conclusions 314 References 315

12 CardiovascularDrugs 331 StephanRiedmaierandUlrichM.Zanger12.1 Introduction 33112.2 RAASasaTargetforAngiotensin-ConvertingEnzymeInhibitorsand

AT1ReceptorBlockers 33112.2.1 ACEInhibitors 33212.2.2 ARBs 33412.3 AdrenergicReceptorAgonists 33712.3.1 α1-SelectiveAdrenergicReceptorAgonists 33712.3.2 α2-SelectiveAdrenergicReceptorAgonists 33812.3.3 β-SelectiveAdrenergicReceptorAgonists 33912.4 AdrenergicReceptorAntagonists 33912.4.1 α1-SelectiveAdrenergicReceptorAntagonists 33912.4.2 α2-SelectiveAdrenergicReceptorAntagonists 34012.4.3 β-SelectiveAdrenergicReceptorAntagonists 34212.5 Diuretics 34212.5.1 CarbonicAnhydraseInhibitors 34412.5.2 OsmoticDiuretics 34412.5.3 Na+–K+–2Cl−SymportInhibitors 34512.5.4 ThiazideorThiazide-LikeDiuretics 34512.5.5 NonspecificCationChannelInhibitors 34712.5.6 InhibitorsofRenalEpithelialNa+Channels 34712.5.7 MineralcorticoidReceptorAntagonists 34812.6 Antiarrhythmics 34912.6.1 CalciumChannelBlockers 34912.7 Anticoagulants 35112.7.1 Heparin 35212.7.2 VitaminKAntagonists 35212.7.3 AntiplateletDrugs 35212.8 Cholesterol-LoweringDrugs 35312.8.1 BileAcidSequestrants 35412.8.2 CholesterolUptakeInhibitors 354

XII Contents

12.8.3 Fibrates 35412.8.4 Statins 355 References 357

13 AnticancerDrugs 365 MatthiasSchwab,ElkeSchaeffeler,andHiltrudBrauch13.1 Introduction 36513.2 AlkylatingDrugs 36513.2.1 Oxazaphosphorine(Cyclophosphamide,Ifosphamide) 36513.2.2 Melphalan 36613.2.3 Ethyleneimines(Thiotepa) 36613.2.4 Busulfan 36613.2.5 Methylhydrazines(Procarbazine) 36713.3 Platinum-ContainingAgents 36713.4 Antimetabolites 36713.4.1 FolicAcidAntagonist(Methotrexate) 36713.4.2 PyrimidineAnalogs(5-Fluorouracil/Capecitabine/Tegafur) 36813.4.3 CytidineAnalogs 36813.4.3.1 CytarabineandGemcitabine 36813.4.3.2 AzacitidineandDecitabine 36913.4.4 PurineAnalogs 36913.4.4.1 6-ThiopurineAnalogs 36913.4.4.2 FludarabinePhosphate 37013.5 NaturalProducts 37013.5.1 VincaAlkaloids(Vincristine) 37013.5.2 Taxanes(Paclitaxel,Docetaxel) 37013.5.3 CamptothecinAnalogs 37113.5.3.1 Topotecan 37113.5.3.2 Irinotecan 37113.5.4 Antibiotics 37113.5.4.1 Dactinomycin 37113.5.4.2 Anthracyclines 37213.5.4.3 Epipodophyllotoxins 37213.6 EndocrineTherapy 37213.6.1 SelectiveEstrogenReceptorModulator(Tamoxifen) 37213.6.2 AromataseInhibitors 37313.7 HistoneDeacetylaseInhibitor(Vorinostat) 37313.8 TyrosineKinaseInhibitors 37313.9 ProteasomeInhibitor(Bortezomib) 374 References 374

14 AntimicrobialAgents 379 ChantalCsajka,OscarMarchetti,OriolManuel,LaurentDecosterd,

andAmalioTelenti14.1 Introduction 379

Contents XIII

14.2 Pharmacokinetics/PharmacodynamicsoftheMainFamiliesofAntimicrobialAgents 380

14.2.1 Aminoglycosides 38014.2.2 Vancomycin 38214.2.3 β-Lactams 38314.2.4 AntifungalAgents 38614.2.5 AntiviralAgents(Non-HIV) 38914.2.5.1 DrugsforHerpesVirusInfection 39014.2.5.2 DrugsforViralHepatitis 39014.2.5.3 DrugsagainstRespiratoryViruses 39114.2.6 Anti-HIVAgents 39114.3 Pharmacogenetics 39314.4 Conclusions 397 Acknowledgments 398 References 398

15 DrugsagainstAcuteandChronicPain 403 AndrewA.SomogyiandJanetK.Coller15.1 Introduction 40315.2 AcutePain 40315.2.1 Dexmedotomidine 40315.2.2 Paracetamol/Acetaminophen 40715.2.3 NonsteroidalAnti-InflammatoryDrugs 40815.2.3.1 Diclofenac 40815.2.3.2 Flurbiprofen 40815.2.3.3 Ibuprofen 40815.2.3.4 Ketoprofen 40915.2.3.5 Ketorolac 40915.2.3.6 Meloxicam 40915.2.3.7 Naproxen 40915.2.4 Cyclooxygenase-2SelectiveInhibitors 41015.2.4.1 Celecoxib 41015.2.4.2 Etoricoxib 41015.2.4.3 Parecoxib 41015.3 ChronicPain 41015.3.1 TricyclicAntidepressants 41015.3.1.1 Amitriptyline 41015.3.1.2 Nortriptyline 41115.3.1.3 Imipramine 41115.3.1.4 Desipramine 41215.3.2 SNRIs 41215.3.2.1 Duloxetine 41215.3.2.2 Venlafaxine 41215.3.3 SSRIs 41315.3.3.1 Citalopram 413

XIV Contents

15.3.3.2 Fluoxetine 41315.3.3.3 Paroxetine 41415.3.4 Ketamine 41415.3.5 Antiepileptics 41515.3.5.1 Carbamazepine 41515.3.5.2 Valproate 41515.3.6 Miscellaneous 41515.3.6.1 Gabapentin 41515.3.6.2 Pregabalin 41515.3.6.3 Tapentadol 41515.3.7 Opioids 41615.3.7.1 Buprenorphine 41615.3.7.2 Butorphanol 41615.3.7.3 Codeine 41615.3.7.4 Dextromoramide 41715.3.7.5 Dextropropoxyphene 41715.3.7.6 Dihydrocodeine 41715.3.7.7 Alfentanil,Fentanyl,Sufentanil,andRemifentanil 41715.3.7.8 Heroin(Diamorphine(3,6-Diacetylmorphine)) 41715.3.7.9 Hydrocodone 41815.3.7.10 Hydromorphone 41815.3.7.11 Ketobemidone 41815.3.7.12 l-α-Acetylmethadol 41815.3.7.13 Levorphanol 41815.3.7.14 Loperamide 41815.3.7.15 Methadone 41915.3.7.16 Morphine 41915.3.7.17 Nalbuphine 41915.3.7.18 Nicomorphine(3,6-Dinicotionylmorphine) 41915.3.7.19 Oxycodone 42015.3.7.20 Oxymorphone 42015.3.7.21 Pentazocine 42015.3.7.22 Pethidine 42015.3.7.23 Piritramide 42015.3.7.24 Tilidine 42015.3.7.25 Tramadol 421 References 421

16 DrugsofAbuse(IncludingDesignerDrugs) 429 MarkusR.MeyerandHansH.Maurer16.1 Introduction 42916.2 ClassicDrugsofAbuse 43216.2.1 MorphineandHeroin 43216.2.2 Cocaine 43216.2.3 THC 433

Contents XV

16.2.4 Amphetamine/Methamphetamine 43416.2.5 LSD 43416.2.6 PCP 43416.3 DesignerDrugsofAbuse 43516.3.1 AmphetamineDerivatives 43516.3.1.1 Methylenedioxyamphetamines 43516.3.1.2 p-SubstitutedAmphetamines 43716.3.1.3 2,5-Dimethoxyamphetamines 43816.3.2 Phenethylamines(2Cs) 43916.3.2.1 2C-B 43916.3.2.2 2C-I 44016.3.2.3 2C-D 44016.3.2.4 2C-E 44016.3.2.5 2C-T-2 44016.3.2.6 2C-T-7 44116.3.2.7 EnzymesInvolvedintheMetabolismof

2,5-Dimethoxyamphetamines 44116.3.3 Cathinones 44116.3.3.1 Methylone 44116.3.3.2 Butylone 44216.3.3.3 Ethylone 44216.3.3.4 Mephedrone 44216.3.4 PhencyclidineDerivatives 44316.3.4.1 N-(1-Phenylcyclohexyl)-3-ethoxypropylamine(PCEPA)

andN-(1-Phenylcyclohexyl)-3-methoxypropanamine(PCMPA) 443

16.3.4.2 N-(1-Phenylcyclohexyl)propanamine(PCPr) 44316.3.4.3 N-(1-Phenylcyclohexyl)-2-ethoxyethanamine(PCEEA)and

N-(1-Phenylcyclohexyl)-2-methoxyethanamine(PCMEA) 44416.3.4.4 EnzymesInvolvedintheMetabolismofPhencyclidine

Derivatives 44416.3.5 Piperazines 44416.3.5.1 N-BZP 44516.3.5.2 1-(3,4-Methylenedioxybenzyl)piperazine(MDBP) 44516.3.5.3 1-(3-Trifluoromethylphenyl)piperazine(TFMPP) 44516.3.5.4 1-(3-Chlorophenyl)piperazine(mCPP) 44616.3.5.5 1-(4-Methoxyphenyl)piperazine(MeOPP) 44616.3.6 Pyrrolidinophenones 44616.3.6.1 α-Pyrrolidinopropiophenone(PPP) 44716.3.6.2 4′-Methoxy-α-pyrrolidinopropiophenone(MOPPP) 44716.3.6.3 Methylenedioxy-α-pyrrolidinopropiophenone(MDPPP) 44716.3.6.4 4′-Methyl-α-pyrrolidinopropiophenone(MPPP) 44816.3.6.5 4′-Methyl-α-pyrrolidinohexanophenone(MPHP) 44816.3.6.6 4′-Methyl-α-pyrrolidinobutyrophenone(MPBP) 44916.3.6.7 4′-Methyl-α-pyrrolidinovalerophenone(PVP) 449

XVI Contents

16.3.6.8 3′,4′-Methylenedioxypyrovalerone(MDPV) 44916.3.7 Tryptamines 45016.3.7.1 5-Methoxy-diisopropyl-tryptamine(5-MeO-DIPT) 450 References 450

17 NicotineMetabolismanditsImplications 465 AndyZ.X.ZhuandRachelF.Tyndale17.1 Introduction 46517.2 AbsorptionandDistributionofNicotine 46517.2.1 Absorption 46517.2.2 Distribution 46617.3 ExcretionofNicotine 46617.4 MetabolismofNicotine 46817.4.1 PrimaryMetabolitesofNicotine 46817.4.2 SecondaryMetabolitesofNicotine 47017.4.3 TertiaryMetaboliteofNicotine 47017.5 SourcesofVariationinNicotineMetabolism 47117.5.1 Genetic 47117.5.1.1 CYP2A6andNicotineC-Oxidation 47117.5.1.2 Usingthe3′-Hydroxycotinine:CotinineRatioasanInVivoProbefor

CYP2A6Activity 47117.5.1.3 InterethnicVariabilityinNicotineC-Oxidation 47617.5.1.4 GeneticInfluencesonOtherNicotine-MetabolizingEnzymes 47617.5.2 GenderandPregnancy 47717.5.3 Age 47817.5.4 MealsandtheChronopharmacokineticsofNicotine 47917.5.5 Xenobiotics 47917.5.6 Smoking 48017.5.7 Menthol 48017.5.8 OtherFactors 48017.6 ImplicationsofVariationinNicotineMetabolismandCYP2A6

Activity 48117.6.1 VariationinNicotineMetabolismisAssociatedwithAltered

SmokingBehaviors 48117.6.2 VariationinNicotineMetabolismMayAltertheHealth

ConsequencesofSmoking 48117.6.3 VariationinNicotineMetabolismAltersSmokingCessation

Outcomes 48217.7 Conclusions 483 Acknowledgments 483 References 484

18 MetabolismofAlcoholanditsConsequences 493 HelmutK.SeitzandSebastianMueller18.1 Introduction 493

Contents XVII

18.2 PropertiesandSourcesofEthanol 49418.2.1 ChemicalPropertiesofEthanol 49418.2.2 EthanolContentofAlcoholicBeverages 49418.2.3 EthanolGenerationintheHumanBody 49418.3 EthanolAbsorptionandElimination 49518.3.1 EthanolAbsorptionandEthanolBloodLevels 49518.3.2 CalculationofEthanolEliminationUsingtheWidmark

Equation 49618.4 EthanolMetabolism 49718.4.1 EthanolMetabolismviaADH 49718.4.2 GastricFPMofEthanol 50218.4.3 EthanolMetabolismviatheMEOS 50418.4.4 EthanolMetabolismviaCatalase 51018.4.5 NonoxidativeMetabolismofEthanol 51018.4.6 AcetaldehydeMetabolismviaALDH 510 Acknowledgments 511 References 511

PartThree MetabolismofNaturalCompounds 517

19 IntroductionandOverview 519 MichaelMurray19.1 Introduction 51919.1.1 SourcesandFunctionalImportanceofNaturalProducts 51919.1.2 PlantProductsasDrugs:AHistoricalPerspective 52019.1.3 ConsiderationswiththeUseofNaturalProductsasDrugs 52019.1.4 BiotransformationofNaturalProducts 52119.1.5 ClassesofNaturalProducts 52119.2 Terpenoids:AStructurallyComplexGroupofNatural

Products 52219.2.1 TerpenoidBiosynthesis 52219.2.2 BiotransformationofTerpenoids 52419.2.2.1 Monoterpenoids 52419.2.2.2 Sesquiterpenoids 52719.2.2.3 Diterpenoids 52819.2.2.4 Triterpenoids 52819.2.2.5 Triterpenoids 53019.3 OtherClassesofNaturalProducts 53119.3.1 BiosynthesisofPolyketides,Shikimates,andAlkaloids 53119.3.2 BiotransformationofImportantPolyketides,Shikimates,and

AlkaloidsinMan 53219.4 SummaryandConclusions 536 Acknowledgments 536 References 536

XVIII Contents

20 Flavonoids 543 PetrHodek20.1 Flavonoids–PlantPhytochemicals 54320.1.1 ClassificationofFlavonoidsandTheirPhysicochemical

Properties 54320.1.2 BiosynthesisofFlavonoidsandTheirBiologicalFunctioninPlants 54520.2 AbsorptionandMetabolismofFlavonoids 54520.2.1 FlavonoidBioavailability 54520.2.2 MetabolismofFlavonoids 54720.2.2.1 IntestinalMetabolism 54820.2.2.2 DecisiveRoleofColonicMicroflora 54920.2.2.3 MetabolisminLiver 54920.2.2.4 FlavonoidExcretion 55020.2.3 OverallFlavonoidFateinOrganisms 55120.2.3.1 PlasmaLevelsandPharmacokineticsofFlavonoids 55320.3 InteractionsofFlavonoidswithMammalianProteinswithPossible

ImplicationsforDrugMetabolism 55420.3.1 PlasmaProteins 55420.3.2 ATP-BindingProteins 55520.3.2.1 MRPs 55520.3.2.2 Kinases 55620.3.3 Flavonoid-BindingReceptors 55720.3.3.1 EstrogenReceptor 55720.3.3.2 GABA-AReceptor 55820.3.3.3 ArylHydrocarbonReceptor 55820.3.4 RedoxEnzymeActivityModulation 55920.3.4.1 Xenobiotic-MetabolizingEnzymes 56020.3.4.2 LOXs,COXs,andXOs 56120.4 DietaryFlavonoids–HealthIssues 56220.4.1 AntioxidantandPro-OxidantProperties 56220.4.2 Antiviral,Antibacterial,andAntifungalAgents 56320.4.3 OtherBiologicalActivitiesofFlavonoids 56420.4.4 FlavonoidsasNutraceuticals 56520.4.4.1 CytotoxicandCytoprotectiveEffects 56620.4.5 FlavonoidInterferencewiththeMetabolismofEndo-and

Xenobiotics 56720.4.5.1 FlavonoidImpactontheMetabolismofEndogenousCompounds 56820.4.5.2 EffectofFlavonoidsonCarcinogenActivation 56820.5 Flavonoid–DrugInteractions 57020.6 Conclusion–Double-EdgedSwordPropertiesofFlavonoids 573 References 574

21 StJohn’sWort(Hypericum perforatumL.) 583 MiroslavDostalekandAnna-KatarinaStark21.1 TheNameHypericum 583

Contents XIX

21.2 ChemicalConstituentsofHypericumperforatum 58321.3 ClinicalPharmacologyofH.perforatum 58721.3.1 AntidepressiveActivity 58721.3.2 PhotodynamicTherapyandCancer 58721.3.3 AntiviralActivity 58721.3.4 OtherPharmacologicalActivities 58721.4 PharmacokineticsandPharmacokineticInteractionsof

H.perforatum 58821.4.1 Phloroglucinols:Hyperforin 58821.4.2 Naphthodianthrones:HypericinandPseudohypericin 58821.4.3 Flavonoids:RutinandQuercetin 58921.5 InVitroStudies 59121.6 InVivoStudies 592 Acknowledgments 592 References 603

22 FoodComponentsandSupplements 611 AlexandrParlesak22.1 Introduction 61122.2 FoodContaminants 61222.2.1 PolycyclicAromaticHydrocarbonsandPolycyclicAromatic

Amines 61222.2.2 Acrylamide 61322.2.3 Nitrosamines 61422.2.4 FungalToxins 61422.3 Vitamins 61622.3.1 VitaminA,RetinoicAcid,andCarotenoids 61622.3.2 VitaminD(CholecalciferolandErgocalciferol) 61822.3.3 VitaminE(Tocopherol) 61922.3.4 Water-SolubleVitamins(ThiamineandRiboflavin) 62022.4 Macronutrients 62022.4.1 Protein 62022.4.2 FattyAcids 62122.4.3 Carbohydrates 62222.5 SecondaryPlantMetabolites 62222.5.1 GrapefruitJuice,Naringenin,andPresystemicDrugClearanceby

CYP3A4 62222.5.2 InhibitionofMetabolicActivationofDrugsbyCYP3A4 62322.5.3 SecondaryPlantMetabolites,CYPModulation,andIntestinal

Inflammation 62322.5.4 ParallelConsumptionofDrugsandInhibitorsofIntestinalDrug

Metabolism–ThreatsandChances 62422.5.5 GlucosinolatesandAllylsulfides 62522.5.6 Caffeine 62622.5.7 Cholesterol 626

XX Contents

22.6 ProbioticsandPrebioticsintheModulationofDrugMetabolism 628

References 629

PartFour MetabolismofUnnaturalXenobiotics 637

23 EnvironmentalPollutants 639 MarieStiborova23.1 Introduction–AnOverview 63923.1.1 TypesofEnvironmentalPollutants 64023.2 OverviewofEnvironmentalPollutants 64123.2.1 AirPollutants 64123.2.2 WaterPollutants 64223.2.3 SoilPollutants 64223.3 ToxicandHazardousEnvironmentalPollutantsInteractingwith

DrugMetabolism 64223.3.1 Acetaldehyde 64223.3.2 Acetonitrile 64323.3.3 2-Acetylaminofluorene 64323.3.4 Acrolein 64323.3.5 Acrylamide 64323.3.6 4-Aminobiphenyl 64423.3.7 o-Anisidine 64423.3.8 Acrylonitrile(2-Propenenitrile) 64423.3.9 ArsenicandArsenicCompounds 64523.3.10 Asbestos 64523.3.11 AntimonyCompounds 64623.3.12 Benzene 64623.3.13 Benzidine 64723.3.14 1,3-Butadiene(VinylEthylene) 64723.3.15 CadmiumCompounds 64723.3.16 CarbonTetrachloride 64823.3.17 CarbonMonoxide 64823.3.18 Chloroform 64923.3.19 Chloroprene 64923.3.20 Cr(VI)Compounds 65023.3.21 CobaltandCobaltCompounds 65023.3.22 1,4-Dichlorobenzene 65123.3.23 1,3-Dichloropropene 65123.3.24 Dichloromethane 65123.3.25 1,1-Dimethylhydrazine 65223.3.26 EthyleneOxide 65223.3.27 Formaldehyde 65223.3.28 Heptachlor 65323.3.29 Hexachlorobenzene 653

Contents XXI

23.3.30 Hydrazine 65423.3.31 LeadandLeadCompounds 65423.3.32 Lindane(AllIsomers) 65523.3.33 MercuryCompounds 65523.3.34 NOx 65623.3.35 Ozone 65623.3.36 Parathion 65623.3.37 Phthalates 65723.3.38 PolycyclicAromaticHydrocarbons 65723.3.39 PolychlorinatedBiphenyls 65823.3.40 PolychlorinatedDioxinsandFurans 65823.3.41 StyreneandStyreneOxide 65923.3.42 SulfurDioxide 65923.3.43 Tetrachloroethylene(Tetrachloroethene,Perchloroethylene) 66023.3.44 VinylChloride 66023.4 Summary 660 References 661

24 EnvironmentalEstrogens 671 MiroslavMachalaandJanVondrácek24.1 Introduction 67124.2 EstrogenReceptorSignalingPathways 67224.3 Agonistic/AntagonisticEffectsofXenobioticsonERs 67324.4 EffectsofEDCsonBiosynthesisandMetabolismofEstrogens 67624.5 CaseofPolychlorinatedBiphenyls 67724.6 Conclusions 678 References 679

25 BiotransformationofInsecticides 685 CorieA.Ellison,AliceL.Crane,andJamesR.Olson25.1 IntroductiontoInsecticides 68525.1.1 OrganophosphateInsecticides 68525.1.2 CarbamateInsecticides 68725.1.3 PyrethroidInsecticides 68725.1.4 OrganochlorineInsecticides 68825.2 MetabolismofInsecticides 68825.2.1 HepaticPhaseIEnzymesInvolvedinBiotransformationof

Insecticides 68825.2.1.1 CytochromeP450s 68825.2.1.2 Flavin-ContainingMonooxygenases 69125.2.1.3 Others 69225.2.2 PhaseIIMetabolismofInsecticides 69225.3 ExtrahepaticMetabolismofInsecticides 69325.4 FactorsAffectingMetabolism 69425.4.1 RouteofExposure 694

XXII Contents

25.4.2 InteractionofXenobiotics 69525.4.3 ImpactofAge,Gender,Species,andPathology 69525.4.4 InterindividualGeneticVariability 69625.5 Conclusions 697 Note 697 References 697

Index 703

XXIII

Preface

Lecturis salutem!The editors of this new book, Metabolism of Drugs and Other Xenobiotics, are

happy to greet all actual and prospective readers.Why is drug metabolism of interest to so many researchers and medical profes-

sionals? Rudolf Buchheim, the founder of modern pharmacology, anticipated one of the major reasons as early as 1859:

In order to understand the actions of drugs it is an absolute necessity to have knowledge of the transformations they undergo in the body. It is obvious that we must not judge drugs according to the form and amount administered, but rather according to the form and amount which actually is eliciting the action. (R. Buchheim, Lehrbuch der Arzneimittellehre, Voss, Leipzig, 1859, p. 19).

However, there are already quite a few books on drug metabolism – so why should there be another one?

One reason is, of course, that new drugs and other xenobiotic chemicals are constantly being produced by our industry; another is the pace of today’s science, which even in a more than a hundred-year-old discipline discovers new fascinating and important facts at exponential speed. However, the most compelling reason, at least to us, was the idea that came up during discussions with Frank Weinreich from Wiley VCH in 2009, to present this wildly complex topic of xenobiotic meta-bolism in a new and more practical way, that is, by drug class. The intention was to give readers the opportunity to get complete information on a given substance in one place (and not distributed among different chapters on enzymes and reac-tions), as well as to compare different substances in the same therapeutic group with respect to their metabolic pathways. Both can be of advantage, for example, to estimate pharmacokinetic variability based on the genetic and non-genetic factors that influence the involved enzyme(s), or to compare alternative drugs with respect to their biotransformation pathways. A further important aspect was not only to cover therapeutic drugs, but also to present a rather comprehensive over-view of the xenobiotic chemical world, including recreational and abused drugs, natural plant and food constituents, as well as industrial chemicals and pollutants.

XXIV Preface

We divided the book’s 25 chapters into four parts: part I contains nine chapters that describe the major drug metabolizing enzyme and transporting protein systems, along with chapters that deal with general aspects of xenobiotic metabo-lism, regulation, and pharmacogenomics. Part II contains, after a general intro-duction, five chapters that describe the metabolism of over 300 clinically used drugs in five major therapeutic groups, as well as unique chapters on the two major socially accepted drugs, nicotine and alcohol, and an overview on illegal drugs of abuse. Part III presents the metabolism of natural compounds, such as plant terpenoids and flavonoids, in addition to food components and supplements, an often neglected area of growing importance. The final section then describes the metabolism of a wide variety of industrial products, environmental pollutants, and agrochemicals such as insecticides.

Nevertheless, the book is by no means exhaustive, and it does not cover the scope extensively, as this would not be possible in a single book. Thus, several important therapeutic areas are not included, and many other xenobiotics from different areas are unmentioned as well. Nevertheless, we hope that the selection we chose provides an interesting read and a useful desktop reference for a diverse spectrum of specialists and researchers, including clinical and experimental phar-macologists, pharmacists or toxicologists, as well as a helpful guide for those who try to find their way into this fascinating field. Although we did our best to avoid mistakes, omissions (particularly of important references), and inconsistencies, we apologize if you may find any.

We would like to express sincere thanks to our contributors. It was not an easy task to cover this broad field but we are confident that they are among the best experts in their fields, and we are very proud to have them as authors. We would also like to thank our co-workers and our families for their patience when we were deeply immersed in the preparation of our chapters and proofs, having even less time for them than usual. Last but not least, this book would not have been pos-sible without the work of numerous people at Wiley VCH, and we would like to thank them all for their cooperation, patience, and tremendously good job.

Pavel Anzenbacher and Uli ZangerOlomouc and Stuttgart, January 2012

XXV

ListofContributors

Pavel AnzenbacherPalacky University at OlomoucFaculty of Medicine and DentistryDepartment of Pharmacology and Inst. Mol. and Translational MedicineHnevotinska st. 3, Olomouc, 775 15Czech Republic

Eva AnzenbacherováPalacky University at OlomoucFaculty of Medicine and DentistryDepartment of Medical Chemistry and BiochemistryHnevotinska st. 3, Olomouc, 775 15Czech Republic

Pierre BaumannUniversité de LausanneCentre Hospitalier Universitaire VaudoisDepartment of PsychiatrySite de Cery1008 Prilly-LausanneSwitzerland

Hiltrud BrauchDr. Margarete Fischer-Bosch Institute of Clinical PharmacologyAuerbachstrasse 11270376 StuttgartGermany

Janet K. CollerUniversity of AdelaideSchool of Medical SciencesDiscipline of PharmacologyAdelaide, 5005Australia

Michael W.H. CoughtrieUniversity of DundeeNinewells Hospital & Medical SchoolMedical Research InstituteDundee, DD1 9SY, ScotlandUK

Alice L. CraneState University of New York at BuffaloDepartment of Pharmacology and ToxicologyBuffalo, NY 14214USA

Chantal CsajkaUniversity of LausanneUniversity Hospital CenterDivision of Clinical Pharmacology and Toxicology1011 LausanneSwitzerland

XXVI ListofContributors

Laurent DecosterdUniversity of LausanneUniversity Hospital CenterDivision of Clinical Pharmacology and Toxicology1011 LausanneSwitzerland

Miroslav DostalekUniversity of Rhode IslandCollege of PharmacyDepartment of Biomedical and Pharmaceutical SciencesClinical Pharmacokinetic Research Laboratory41 Lower College RoadKingston, RI 02881USASimcyp LimitedBlades Enterprise CentreJohn StreetS2 4SU SheffieldUK

Zdenek DvorakPalacky UniversityFaculty of ScienceDepartment of Cell Biology and GeneticsSlechtitelu 11783 71 OlomoucCzech Republic

Corie A. EllisonState University of New York at BuffaloDepartment of Pharmacology and ToxicologyBuffalo, NY 14214USA

F. Peter GuengerichVanderbilt University School of MedicineDepartment of Biochemistry and Center in Molecular Toxicology638 Robinson Research Building2200 Pierce AvenueNashville, TN 37232-0146USA

Christoph HiemkeKlinik für Psychiatrie und PsychotherapieUniversitätsmedizin MainzUntere Zahlbacher Str. 855131 MainzGermany

Petr HodekCharles University PragueDepartment of BiochemistryAlbertov 2030Prague, 128 40 Praha 2Czech Republic

Sandra KalthoffProfessor of Gastroenterology and HepatologyHannover Medical SchoolDepartment of Gastroenterology, Hepatology and EndocrinologyCarl-Neuberg-Str. 130625 HannoverGermany

Kathrin KleinDr. Margarete Fischer-Bosch Institute of Clinical PharmacologyAuerbachstrasse 11270376 StuttgartGermany

ListofContributors XXVII

Miroslav MachalaVeterinary Research InstituteDepartment of Toxicology, Pharmacology and ImmunotherapyHudcova 70621 00 BrnoCzech Republic

Oriol ManuelUniversity Hospital CenterService of Infectious Diseases and Transplantation Center1011 LausanneSwitzerland

Oscar MarchettiUniversity of LausanneUniversity Hospital CenterService of Infectious Diseases1011 LausanneSwitzerland

Hans H. MaurerSaarland UniversityInstitute of Experimental and Clinical Pharmacology and ToxicologyDepartment of Experimental and Clinical Toxicology66421 Homburg (Saar)Germany

Markus R. MeyerSaarland UniversityInstitute of Experimental and Clinical Pharmacology and ToxicologyDepartment of Experimental and Clinical Toxicology66421 Homburg (Saar)Germany

Sebastian MuellerUniversity of HeidelbergCentre of Alcohol Research and Salem Medical CentreDepartment of MedicineZeppelinstraße 11-3369121 HeidelbergGermany

Michael MurrayUniversity of SydneyFaculty of PharmacyPharmacogenomics and Drug Development GroupSydney, NSW 2006Australia

Tadashi NamisakiDr. Margarete Fischer-Bosch Institute of Clinical PharmacologyAuerbachstrasse 11270376 StuttgartGermany

Anne T. NiesDr. Margarete Fischer-Bosch Institute of Clinical PharmacologyAuerbachstrasse 11270376 StuttgartGermany

James R. OlsonState University of New York at BuffaloDepartment of Pharmacology and Toxicology/Department of Social and Preventive MedicineBuffalo, NY 14214USA

XXVIII ListofContributors

Alexandr ParlesakTechnical University of DenmarkDepartment of Systems BiologySøltofts PladsBldg. 2242800 LyngbyDenmark

Claudia ReschDr. Margarete Fischer-Bosch Institute of Clinical PharmacologyAuerbachstrasse 11270376 StuttgartGermany

Stephan RiedmaierDr. Margarete Fischer-Bosch Institute of Clinical PharmacologyAuerbachstrasse 11270376 StuttgartGermany

Jessica RiegerDr. Margarete Fischer-Bosch Institute of Clinical PharmacologyAuerbachstrasse 11270376 StuttgartGermany

Elke SchaeffelerDr. Margarete Fischer-Bosch Institute of Clinical PharmacologyAuerbachstrasse 11270376 StuttgartGermany

Matthias SchwabDr. Margarete Fischer-Bosch Institute of Clinical PharmacologyAuerbachstrasse 11270376 StuttgartGermanyandInstitute of Experimental and Clinical Pharmacology and ToxicologyDepartment of Clinical PharmacologyUniversity HospitalOtfried-Müller-Str. 4572076 TübingenGermany

Helmut K. SeitzUniversity of HeidelbergCentre of Alcohol Research and Salem Medical CentreDepartement of MedicineZeppelinstraße 11-3369121 HeidelbergGermany

Andrew A. SomogyiUniversity of AdelaideSchool of Medical SciencesDiscipline of PharmacologyAdelaide, 5005Australia

Anna-Katarina StarkKarolinska InstitutetNational Institute of Environmental Medicine171 11 StockholmSweden

Marie StiborovaCharles University PragueDepartment of BiochemistryAlbertov 2030Prague, 128 40 Praha 2Czech Republic