Pharmacokinetics, Metabolism, and

Pharmaceutics of

Drugs of Abuse

Editors:

Rao S. Rapaka, Ph.D.

Division of Basic Research

National Institute on Drug Abuse

Nora Chiang, Ph.D.

Medications Development Division

National Institute on Drug Abuse

and

Billy R. Martin, Ph.D.

Department of Pharmacology

Virginia Commonwealth University

NIDA Research Monograph 173

1997

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

National Institute on Drug Abuse

Division of Clinical Research

5600 Fishers Lane

Rockville, MD 20857
ii

ACKNOWLEDGMENT

This monograph is based on the papers from a

technical review on "Metabolism, Pharmacokinetics,

and Pharmacodynamics of Drugs of Abuse" held on

November 4-5, 1994. The review meeting was

sponsored by the National Institute on Drug Abuse.

COPYRIGHT STATUS

The National Institute on Drug Abuse has obtained

permission from the copyright holders to reproduce

certain previously published material as noted in the

text. Further reproduction of this copyrighted

material is permitted only as part of a reprinting of

the entire publication or chapter. For any other use,

the copyright holder's permission is required. All

other material in this volume except quoted passages

from copyrighted sources is in the public domain and

may be used or reproduced without permission from

the Institute or the authors. Citation of the source is

appreciated.

Opinions expressed in this volume are those of the

authors and do not necessarily reflect the opinions or

official policy of the National Institute on Drug Abuse

or any other part of the U.S. Department of Health

and Human Services.

The U.S. Government does not endorse or favor any

specific commercial product or company. Trade,

proprietary, or company names appearing in this

publication are used only because they are considered

essential in the context of the studies reported herein.

National Institute on Drug Abuse

NIH Publication No. 97-4141

Printed 1997

NIDA Research Monographs are indexed in the Index Medicus. They are

selectively included in the coverage of American Statistics Index,

BioSciences Information Service, Chemical Abstracts, Current Contents,

Psychological Abstracts, and Psychopharmacology Abstracts.
iii

Table of Contents

Click on page number or title to go to that section

Introduction......................................................................................1

Rao S. Rapaka, Nora Chiang, and Billy R. Martin

The Potential Role of the Cytochrome P-450 2D6 Pharmacogenetic

Polymorphism in Drug Abuse............................................................6

Edward M. Sellers, S. Victoria Otton, and Rachel F. Tyndale

Human Liver Cocaine Carboxylesterases..........................................27

William F. Bosron, Robert A. Dean, Monica R. Brzezinski, and

Evgenia V. Pindel

Effects of Ethanol on Cocaine Metabolism and

Disposition in the Rat......................................................................35

Robert A. Dean, William F. Bosron, Frederick M. Zachman, Jing

Zhang, and Monica R. Brzezinski

Individual Differences in Nicotine Kinetics and

Metabolism in Humans....................................................................48

Neal L. Benowitz and Peyton Jacob III

Inhibitors of Anandamide Breakdown..............................................65

Dale G. Deutsch and Alexandros Makriyannis

Metabolic Bioactivation Reactions Potentially Related to

Drug Toxicities................................................................................85

Neal Castagnoli, Jr. and Kay P. Castagnoli

The Role of Iminium-Enamine Species in the Toxication and

Detoxication of Cyclic Tertiary Amines........................................106

Lawrence M. Sayre, David A. Engelhart, Durgesh V. Nadkarni,

M.K. Manoj Babu, Ann Marie Flammang, and G. David McCoy

Neurotoxicity of Amphetamines and Their Metabolites................128

James W. Gibb, Michel Johnson, Ikram Elayan,

Heng Keang Lim, Lisa Matsuda, and Glen R. Hanson
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Potential New Insights Into the Molecular Mechanisms of

Methamphetamine-Induced Neurodegeneration.............................146

Monika Z. Wrona, Zhaoliang Yang, Fa Zhang, and

Glenn Dryhurst

Immunotoxicology of Opioids, Inhalants, and

Other Drugs of Abuse.....................................................................175

Robert V. House, Peter T. Thomas, and Hemendra N. Bhargava

Inhalation Studies With Drugs of Abuse.........................................201

Yun Meng, Aron H. Lichtman, D. Troy Bridgen, and

Billy R. Martin

Biocatalysts in Detoxication of Drugs of Abuse.............................225

John R. Cashman

Antibodies as Pharmacokinetic and Metabolic Modifiers of

Neurotoxicity................................................................................259

S. Michael Owens

Toxicokinetics in the National Toxicology Program.....................273

Thomas J. Goehl