Pharmacokinetics, Metabolism, and Pharmaceutics of Drugs ...
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
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.
ii
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
iii
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
iv
Introduction
Rao S. Rapaka, Nora Chiang, and Billy R. Martin
Drugs of abuse represent a wide array of chemical classes. Therefore,
it is not surprising that the consequences of drug abuse are highly
dependent upon the chemical in question and vary considerably across
drug classes. During the past decade, understanding of the actions of
these drugs at the molecular and cellular levels has increased
dramatically, thereby providing insight into developing new strategies
for the treatment of drug dependence. However, the interaction of a
drug with a particular biochemical system is only one factor to be
considered when evaluating the pathological impact of substance
abuse. The route of administration, the pharmacokinetics of the drug,
conversion to toxic metabolites, and interindividual responsive-ness
are just a few factors. The objective of this monograph is to evaluate
the current status of knowledge of metabolism, pharmacokinetics, and
pharmacodynamics of drugs of abuse. The overall goal is to identify
innovative approaches for the management and treatment of the
adverse consequence produced by drugs of abuse.
One of the most important challenges of drug abuse research has been
providing an explanation for why all individuals do not respond or
react in a similar fashion to a drug. Metabolism plays a critical role in
the pharmacological and toxicological consequences of drug exposure.
It is well known that the rate of formation of active, inactive, or
toxic metabo-lites varies among individuals. The past decade has been
marked by the characterization of substrate specificity for a large
number of P-450 enzymes and the development of biochemical tools
for quantitation of these enzyme levels. These advances have allowed
determination of the role of metabolic enzymes in susceptibility to
drug dependence, metabolic tolerance, and variability in the toxic
consequence of exposure.
The future holds great promise for utilizing a "fingerprint" of P-450
enzymes as genetic markers for predisposition to either enhanced or
diminished drug dependence. It is also becoming increasingly clear
that brain metabolism has a more prominent role than previously
thought. Notable examples include opioid, amphetamine, nicotine,
and cocaine metabolism by specific isozymes to varying degrees in
different organs. Both synthetic and degradative enzymes for
neurotransmitters and endogenous ligands, including the putative
endogenous cannabinoid ligand anandamide, deserve attention. Future
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