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

1

 ................
................

In order to avoid copyright disputes, this page is only a partial summary.

Google Online Preview   Download