Drug Metabolizing Enzymes: Cytochrome P450 and Other Enzymes in Drug Discovery and Development

by Lee; Jae

• ISBN13: 9780824742935
• ISBN10: 0824742931
• Format: Hardcover
• Copyright: 2003-09-03
• Publisher: CRC Press

Summary

(Fontis Media) Summarizes the latest findings on P450 and similar enzymes for promoting the next generation of safer, more effective drugs. Discusses P450 in experimental animals, bioactivation and human drug clearance, enzyme kinetics and P450 reaction phenotyping, P450 in drug-drug interactions, and non-P-450 mediated metabolism of xenobiotics.

Table of Contents

Editors' Preface	xiii
Foreword	xv
Anthony Y.H. Lu
Chapter 1 DIOXYGEN ACTIVATION BY CYTOCHROMES P450: A ROLE FOR MULTIPLE OXIDANTS IN THE OXIDATION OF SUBSTRATES	1	(32)
Alfin D.N. Vaz
1 INTRODUCTION	1	(5)
1.1 Ligands to heme in CYP enzymes	2	(1)
1.2 Reaction cycle of CYP enzymes	3	(3)
2 ACTIVE OXIDANT(S) IN CYP REACTIONS	6	(13)
2.1 Heme-oxene as oxidant	6	(5)
2.2 Heme-peroxo as an oxidant	11	(6)
2.3 Multiple Oxidant Hypothesis in CYP-catalyzed oxidations	17	(2)
3 HEME-HYDROPEROXO AS AN OXIDANT	19	(5)
4 HEME-SUPEROXO AS ACTIVE OXIDANT	24	(1)
5 THE TWO-STATE THEORY	25	(2)
CONCLUSIONS	27	(1)
REFERENCES	27	(6)
Chapter 2 APPLICATION OF LC/MS, LC/NMR, NMR AND STABLE ISOTOPES IN IDENTIFYING AND CHARACTERIZING METABOLITES	33	(54)
A.E. Mutlib and John P. Shockcor
1 INTRODUCTION	33	(3)
2 SEPARATION OF METABOLITES FROM ENDOGENOUS COMPONENTS	36	(3)
2.1 Sample Clean-up on Solid Phase Cartridges	37	(2)
3 LIQUID CHROMATOGRAPHY/MASS SPECTROMETRY	39	(7)
4 NUCLEAR MAGNETIC RESONANCE (NMR)	46	(5)
4.1 Continuous-Flow LC-NMR	46	(1)
4.2 Time-Slice LC-NMR	47	(1)
4.3 Stop-Flow LC-NMR	47	(2)
4.4 Loop-Storage	49	(1)
4.5 LC-NMR-MS	49	(1)
4.6 Recent Advances in NMR	50	(1)
5 SPECIFIC EXAMPLES	51	(30)
5.1 Metabolism of Efavirenz (DPC 266) and Renal Toxicity	51	(3)
5.2 Characterization of Unusual Metabolites	54	(26)
5.3 Pharmacologically Active Metabolites	80	(1)
6 CONCLUSIONS	81	(2)
REFERENCES	83	(4)
Chapter 3 BIOACTIVATION	87	(60)
Jack Uetrecht
1 INTRODUCTION	87	(1)
2 INVOLVEMENT OF REACTIVE METABOLITES IN ADVERSE REACTIONS	88	(5)
2.1 Types of Adverse Drug Reactions	88	(1)
2.2 The Hapten Hypothesis	89	(2)
2.3 The Danger Hypothesis	91	(1)
2.4 Immune Response in the Absence of Covalent Binding	92	(1)
3 ENZYME SYSTEMS RESPONSIBLE FOR METABOLIC ACTIVATION	93	(1)
4 TYPES OF REACTIVE METABOLITES	94	(41)
4.1 General Types of Reactive Metabolites	94	(2)
4.2 Alkyl Halides	96	(1)
4.3 Primary Aryl Amines	97	(4)
4.4 Aromatic Nitro Drugs	101	(3)
4.5 Hydrazines	104	(2)
4.6 Other Nitrogen-Containing Aromatic Compounds	106	(1)
4.7 Acyl Glucuronides and Co-A Esters	107	(3)
4.8 Quinone-type Reactive Metabolites	110	(11)
4.10 Metabolites, such as Epoxides, that are Reactive because of Ring Strain	121	(4)
4.11 Furans and Thiophenes	125	(1)
4.12 Sulfhydryl-Containing Drugs	126	(1)
4.13 Thiono Sulfur Compounds	127	(2)
4.14 Isocyanates	129	(2)
4.15 Acetylenes	131	(1)
4.16 Methylenedioxyphenyl compounds	131	(1)
4.17 Free Radicals	132	(3)
5 THE USE OF BIOACTIVATION SCREENS FOR LEAD DRUG SELECTION	135	(3)
6 SUMMARY AND CONCLUSIONS	138	(1)
REFERENCES	139	(8)
Chapter 4 CHEMICALLY REACTIVE METABOLITES IN DRUGDISCOVERY AND DEVELOPMENT	147	(8)
Thomas A. Baillie
REFERENCES	154	(1)
Chapter 5 CYTOCHROME P450 AND ITS PLACE IN DRUG DISCOVERY AND DEVELOPMENT	155	(24)
Dennis Smith
INTRODUCTION	155	(1)
1 FROM SINGLE ENZYME TO SUPERFAMILY OF HUMAN ISOFORMS	155	(5)
2 INHIBITION OF HUMAN ISOFORMS	160	(3)
3 INDUCTION OF HUMAN ISOFORMS	163	(3)
4 DIVERSITY OF HUMAN ISOFORMS	166	(2)
5 RESPONSE TO P450 METABOLISM IN DRUG DESIGN	168	(5)
6 P450 AS A DRUG TARGET	173	(3)
7 SUMMARY	176	(1)
REFERENCES	176	(3)
Chapter 6 CYTOCHROME P450 IN LABORATORY ANIMAL SPECIES	179	(32)
Margit Spatzenegger, Stephanie L. Born and James R. Halpert
1 INTRODUCTION	179	(1)
2 LABORATORY ANIMAL MODELS AS PREDICTORS OF HUMAN METABOLISM	179	(6)
2.1 Basic Approaches	180	(2)
2.2 Interspecies Scaling	182	(3)
3 FROM ANIMAL TO MAN: COMPARISON OF CATALYTIC SELECTIVITY BY ONE SUBFAMILY	185	(7)
3.1 CYP1A	185	(1)
3.2 CYP2A	186	(1)
3.3 CYP2B	187	(1)
3.4 CYP2C	188	(1)
3.5 CYP2D	189	(1)
3.6 CYP2E	189	(1)
3.7 CYP3A	190	(1)
3.8 CYP4A	191	(1)
4 REGULATION OF LABORATORY ANIMAL CYTOCHROME P450	192	(5)
4.1 Regulation of CYP1 genes	192	(1)
4.2 Regulation of CYP2B genes	193	(2)
4.3 Regulation of CYP3A genes	195	(1)
4.4 Regulation of CYP4A genes	196	(1)
5 NON-NATIVE ANIMAL MODELS	197	(4)
5.1 The Gene Knockout Mouse Model	197	(3)
5.2 The Humanized Mouse Model	200	(1)
6 CONCLUSIONS	201	(1)
REFERENCES	202	(9)
Chapter 7 TYPICAL AND ATYPICAL ENZYME KINETICS	211	(44)
J. Brian Houston, Kathryn E. Kenworthy and Aleksandra Galetin	211	(44)
1 INTRODUCTION	212	(3)
1.1 General considerations of In Vitro Experimentation	213	(2)
1.2 Scope of this chapter	215	(1)
2 THE MICHAELIS-MENTEN APPROACH FOR ANALYSIS OF ENZYME KINETIC DATA	215	(12)
2.1 Enzyme Kinetic Studies in Drug Metabolism	216	(1)
2.2 Assumptions in Enzyme Kinetics	216	(1)
2.3 Methodological Considerations	217	(1)
2.4 Analysis of Substrate Kinetic Data	218	(5)
2.5 Analysis of Enzyme Inhibition Data	223	(4)
3 MULTISITE APPROACH FOR ANALYSIS OF A TYPICAL KINETIC DATA	227	(21)
3.1 Homotropic Effects	229	(6)
3.2 Heterotropic Effects	235	(11)
3.3 Criteria for Selection of an Appropriate Multisite Kinetic Model in Prediction of Drug Interactions	246	(2)
4 IN VIVO RELEVANCE OF IN VITRO ATYPICAL KINETICS AND CURRENT PERSPECTIVE	248	(3)
REFERENCES	251	(4)
Chapter 8 CYTOCHROME P450 REACTION PHENOTYPING	255	(56)
Larry C. Wienkers and Jeffrey C. Stevens
1 INTRODUCTION	256	(6)
2 EFFECT OF INCUBATION CONDITIONS ON REACTION PHENOTYPING	262	(4)
3 ENZYME KINETICS AND REACTION PHENOTYPING	266	(8)
4 CORRELATION ANALYSIS	274	(7)
5 EXPRESSED P450S AND REACTION PHENOTYPING	281	(4)
6 CHEMICAL INHIBITORS AND REACTION PHENOTYPING	285	(9)
7 ANTIBODIES	294	(5)
8 CONCLUDING REMARKS	299	(1)
9 ACKNOWLEDGEMENTS	300	(1)
REFERENCES	300	(11)
Chapter 9 DRUG-DRUG INTERACTIONS AND THE CYTOCHROMES P450	311	(26)
Kenneth A. Bachmann, Barbara J. Ring and Steven A. Wrighton
1 INTRODUCTION	311	(6)
1.1 The Numerology of Drug-Drug Interactions	311	(1)
1.2 The Centrality of the Cytochromes P450 in Drug-Drug Interactions	312	(2)
1.3 Clinical Ramifications of CYP-Based Drug-Drug Interactions	314	(1)
1.4 Electronic Sources of Information on CYP-Based Drug-Drug Interactions	315	(2)
2 IN VITRO DRUG-DRUG INTERACTIONS: DETERMINING THE POTENTIAL OF AN NCE TO INHIBIT THE CYPS	317	(5)
2.1 In Vitro to In Vivo Extrapolations	319	(2)
2.2 Irreversible or Quasi-Irreversible Inhibition	321	(1)
3 IN VIVO DRUG-DRUG INTERACTION STUDIES	322	(10)
3.1 CYP-Based Interactions with Nutraceuticals and Food	327	(3)
3.2 Transporter-Mediated Drug-Drug Interactions Masquerading as CYP-Based Interactions	330	(1)
3.3 Pharmacogenetics and CYP-Based Drug-Drug Interactions	331	(1)
4 CONCLUSION	332	(1)
REFERENCES	332	(5)
Chapter 10 CYP GENE INDUCTION BY XENOBIOTICS AND DRUGS	337	(38)
Academic authors: Jean-Marc Pascussi, Sabine Gerbai-Chaloin, Martine Daujat, Lionel Drocourt, Lydiane Pichard-Garcia, Marie-José Vilarem and Patrick Maurel
Drug Industry authors: Sylvie Klieber, François Torreilles, Martine Bourne, François Guillou and Gérard Fabre
1 INTRODUCTION	337	(1)
2 CLINICAL AND PHARMACOLOGICAL CONSEQUENCES OF CYP 1-3 GENE INDUCTION IN MAN	338	(1)
3 MECHANISMS OF CYP GENE INDUCTION	339	(15)
3.1 Induction of the CYP1A family	339	(1)
3.2 Cross-talks between the AhR pathway and other transcriptional factors and signal transduction pathways	340	(4)
3.3 Induction of CYP2 and CYP3 families	344	(5)
3.4 Cross-talk between PXR and CAR	349	(1)
3.5 Cross-talk between PXR and CAR and other nuclear receptors	350	(4)
4 IN VITRO SYSTEMS TO SCREEN CYP INDUCERS	354	(6)
4.1 Direct receptor-ligand binding assays	355	(1)
4.2 Enhanced green fluorescent protein (EGFP)-based recombinant cell bioassay	356	(1)
4.3 Ligand-induced receptor-coactivator interaction assays	356	(1)
4.4 Cell lines for the direct screening of CYP1A inducers	357	(1)
4.5 Cell line co-transfections: gene reporter assays	358	(1)
4.6 Primary human hepatocytes for the direct screening of CYP inducers	359	(1)
5 IN VIVO EVALUATION OF CYP INDUCTION IN MAN	360	(4)
5.1 Induction of CYP1A2 isoform	361	(1)
5.2 Induction of CYP3A4 isoform	362	(2)
6 CONCLUSION	364	(1)
REFERENCES	365	(10)
Chapter 11 CYTOCHROME P450 PHARMACOGENETICS	375	(46)
Robert L. Haining and Aiming Yu
1 INTRODUCTION	375	(6)
1.1 Chapter Introduction	375	(1)
1.2 Brief History of Pharmacogenetics	375	(1)
1.3 Fundamentals of Pharmacogenetic Mutations	376	(4)
1.4 In Vivo versus In Vitro Considerations	380	(1)
1.5 Key principles of pharmacogenetics	380	(1)
2 P450 PHARMACOGENETICS	381	(31)
2.1 CYP2C9 and Warfarin	381	(4)
2.2 The CYP2D6 Story	385	(16)
2.3 Other Human Cytochrome P450s of Real and/or Potential Pharmacogenetic Interest	401	(11)
3 PHARMACOGENETICS: PROMISE VERSUS PRACTICE	412	(2)
4 CONCLUSIONS	414	(1)
ACKNOWLEDGEMENT	415	(1)
REFERENCES	415	(6)
Chapter 12 ROLE OF INTESTINAL CYTOCHROMES P450 IN DRUG DISPOSITION	421	(32)
Mary F. Paine and Kenneth E. Thummel	421	(32)
1 INTRODUCTION	422	(7)
1.1 Absorption and the First-Pass Effect	422	(1)
1.2 Drug Movement Through the Gastrointestinal Barrier	423	(1)
1.3 Anatomic and Physiologic Considerations	424	(2)
1.4 Clinical Relevance of Intestinal First-Pass Metabolism	426	(2)
1.5 Overview of Intestinal Drug Metabolizing Enzymes	428	(1)
2 INTESTINAL CYTOCHROMES P450	429	(16)
2.1 Individual Subfamilies/Isoforms	430	(15)
3 SUMMARY AND PERSPECTIVE	445	(1)
REFERENCES	446	(7)
Chapter 13 PREDICTION OF HEPATIC CLEARANCE IN HUMANS FROM EXPERIMENTAL ANIMALS AND IN VITRO DATA	453	(30)
Masato Chiba, Yoshihiro Shibata, Hiroyuki Takahashi, Yasuyuki Ishii and Yuichi Sugiyama
1 INTRODUCTION	454	(4)
2 STRATEGY FOR THE PREDICTION OF HEPATIC CLEARANCE IN HUMANS	458	(16)
2.1 Allometric Scaling Methods to predict Clearance in Humans	458	(5)
2.2 Direct Prediction of Hepatic Clearance in Humans and Experimental Animals from In-vitro Liver Microsomal Data	463	(5)
2.3 Empirical Prediction of Hepatic Clearance in Humans by In Vitro-In Vivo Relationship in Experimental Animals	468	(2)
2.4 Empirical Prediction of Hepatic Clearance in Humans by In Vitro-In Vivo Calibration of Human Hepatocytes Data	470	(4)
3 OPTIMIZATION OF METABOLIC CLEARANCE BY STRUCTURE MODIFICATION	474	(3)
4 CONCLUSION	477	(1)
REFERENCES	478	(5)
Chapter 14 NON-P450 MEDIATED OXIDATIVE METABOLISM OF XENOBIOTICS	483	(58)
Dieter Lang and Amit S. Kalgutkar
1 FLAVIN-CONTAINING MONOOXYGENASES (FMOS)	484	(15)
1.1 Nomenclature and Molecular Characteristics of FMOs	484	(1)
1.2 Tissue Distribution and Species Differences of FMOs	485	(1)
1.3 Regulation of FMO Expression	486	(2)
1.4 Catalytic Mechanism	488	(1)
1.5 Characteristics of FMO Catalyzed Reactions	489	(5)
1.6 Diagnostic Tools to Distinguish P450- and FMO-Catalyzed Reactions	494	(2)
1.7 Diagnostic FMO Substrates In Vitro and In Vivo	496	(2)
1.8 Polymorphism of Human FMOs and Relevance of FMOs to Drug Metabolism	498	(1)
2 MONOAMINE OXIDASES	499	(12)
2.1 Multiplicity, Tissue Distribution, and Species Differences for the Mammalian Isozymes	499	(2)
2.2 Crystal Structure	501	(1)
2.3 Catalysis	501	(2)
2.4 SAR Analysis of MAO Substrates	503	(5)
2.5 MAO Inhibition	508	(3)
2.6 MAO and Drug Metabolism	511	(1)
3 MOLYBDENUM HYDROXYLASES	511	(16)
3.1 Tissue Distribution	513	(1)
3.2 Species Distribution	514	(1)
3.3 Catalysis	515	(1)
3.4 Substrate Specificity of Molybdenum hydroxylases	516	(5)
3.5 Antiviral Prodrug Activation by AO and XO	521	(1)
3.6 Molybdenum Hydroxylase Mediated Reductions	522	(3)
3.7 Inhibitors of Molybdenum Hydroxylases	525	(1)
3.8 Molybdenum Hydroxylases and Drug Metabolism	526	(1)
4 CARBONYL REDUCTASES AND ALCOHOL- AND ALDEHYDE DEHYDROGENASES	527	(2)
4.1 Alcohol Dehydrogenases	527	(1)
4.2 Aldehyde Dehydrogenases	527	(1)
4.3 Carbonyl Reductases	528	(1)
REFERENCES	529	(12)
Chapter 15 THE ROLE OF SULFORTRANSFERASES (SULTS) AND UDPGLUCURONOSYLTRANSFERASES (UGTS) IN HUMAN DRUG CLEARANCE AND BIOACTIVATION	541	(36)
Michael W.H. Coughtrie and Michael B. Fisher
GENERAL INTRODUCTION	541	(1)
INTRODUCTION TO THE SULFOTRANSFERASE ENZYME FAMILY	541	(1)
1 ASSAY OF SULFOTRANSFERASE ENZYME FAMILY	541	(4)
2 MOLECULAR TOOLS AVAILABLE TO STUDY SULFOTRANSFERASES	545	(3)
3 ROLE OF SULFATION IN BIOACTIVATION OF DRUGS AND OTHER XENOBIOTICS	548	(2)
4 SULFOTRANSFERASE PHARMACOGENETICS	550	(1)
5 INTRODUCTION TO THE UDP-GLUCURONOSYLTRANSFERASE ENZYME FAMILY	551	(1)
6 REACTION MECHANISM/STRUCTURE	552	(2)
7 ENZYMOLOGY AND METHODOLOGIES	554	(3)
8 REGULATION	557	(1)
9 PHARMACOGENETICS	558	(3)
10 ROLE IN DRUG AND XENOBIOTIC METABOLISM	561	(5)
10.1 Bioactivation	561	(2)
10.2 Structure-biotransformation relationships.	563	(1)
10.3 Kinetics and scaling.	564	(1)
10.4 First-pass metabolism.	565	(1)
11 CONCLUSIONS	566	(11)
ACKNOWLEDGEMENTS	567	(1)
REFERENCES	567	(10)
INDEX	577