Membranes and Barriers: Targeted Drug Delivery,” and Details of Those Studies Can Be Found in This Monograph

National Institute on Drug Abuse RESEARCH MONOGRAPH SERIES Membranes and Barriers: Targeted Drug Delivery U.S. Department of Health and Human Services1 • Public5 Health Service4 • National Institutes of Health Membranes and Barriers: Targeted Drug Delivery Editor: Rao S. Rapaka, Ph.D. NIDA Research Monograph 154 1995 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service National Institutes of Health National Institute on Drug Abuse Division of Preclinical Research 5600 Fishers Lane Rockville, MD 20857 ACKNOWLEDGMENT This monograph is based on the papers from a technical review on “Membranes and Barriers: Targeted Drug Delivery” held on September 28-29, 1993. 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. 95-3889 Printed 1995 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 Contents Retrometabolic Approaches to Drug Targeting . 1 Nicholas Bodor Vector-Mediated Delivery of Opioid Peptides to the Brain . 28 Ulrich Bickel and William M. Pardridge Conformationally Constrained Peptide Drugs Targeted at the Blood-Brain Barrier . 47 Thomas P. Davis, Thomas J. Abbruscato, Elizabeth Brownson, and Victor J. Hruby Passive and Facilitative Transport of Nucleobases, Nucleosides, and Oligonucleotides—Application to Antiviral and Other Therapies . 61 Marcus E. Brewster and Nicholas Bodor Oral Peptide Delivery: Improving the Systemic Availability of Small Peptides and Enkephalin Analogs . 86 Hye J. Lee and Gordon L. Amidon The Use of Polymers in the Construction of Controlled-Release Devices . 107 Jorge Heller Pharmacokinetics and Pharmacodynamics of Maternal-Fetal Transport of Drugs of Abuse: A Critical Review . 132 Srikumaran Melethil Placental Permeability for Drugs of Abuse and Their Metabolites . 152 George D. Olsen Pharmacodynamics in the Maternal-Fetal-Placental Unit . 163 Abraham M. Rudolph New Approaches for Drug and Kinetic Analysis in the Maternal-Fetal Unit . 175 George R. Tonn, Ahmad Doroudian, John G. Gordon, Dan W. Rurak, K. Wayne Riggs, Frank S. Abbott, and James E. Axelson iii Maternal-Fetal Pharmacokinetics: Summary and Future Directions . 203 Hazel H. Szeto Technical Issues Concerning Hair Analysis for Drugs of Abuse . 218 Martha R. Harkey Models for Studying the Cellular Processes and Barriers to the Incorporation of Drugs Into Hair . 235 Douglas E. Rollins, Diana G. Wilkins, and Gerald Krueger iv Retrometabolic Approaches to Drug Targeting Nicholas Bodor INTRODUCTION Targeted drug delivery is the most important goal of pharmaceutical research and development. In this context drug targeting is defined in the broadest sense, that is, to optimize a drug’s therapeutic index by strictly localizing its pharmacological activity to the site or organ of action. This is an important distinction from the basic targeting concept, where the specific drug receptor is the target and the objective is to improve fit, affinity, and binding to the specific receptor that ultimately will trigger the pharmacological activity. This distinction is made since the overall distribution of many drug receptors does not follow the various diseases. Actually, most of the time, drug toxicity is receptor related and receptor mediated; thus, improving intrinsic drug affinity and activity, as well as receptor binding, does not improve the therapeutic index. In principle, drug targeting can be achieved by physical, biological, or molecular systems that result in high concentrations of the pharmaco- logically active agent at the pathophysiologically relevant site. If successful, the result of the targeting would be a significant reduction in drug toxicity, reduction of the drug dose, and increased treatment efficacy. All in all, it is evident that with a biologically active agent of reasonable activity at hand, targeting to the site of action should be superior to molecular manipulations aimed at refining the receptor substrate interactions. Successful drug targeting, however, is a very complicated problem. It involves affecting the various distributional and rate processes, as well as sometimes the drug metabolism and disposition, as will be shown. There are a number of important parameters to be considered in designing drug targeting of any kind. These include the nature of biological and cellular membranes, distribution and presence of drug receptors, as well as the enzymes responsible for drug metabolism, time-plasma concentration profiles, and local blood flow. A tremendous amount of work has been concentrated worldwide in the past two decades on the research and development of drugs with improved site-specificity, that is, targeted drug delivery systems. Although the concept of a “magic bullet” has been around for almost 100 years, scientists involved in drug research and discovery simply did not have the basic means and concepts to achieve this elusive goal. The advancement of the drug receptor concept and then specific knowledge about the various receptors suggested that this is the direction that should be taken for drug targeting. However, as mentioned before, the receptors alone, due to their distributional properties, cannot be responsible for selectivity and drug targeting. There were a number of major steps in drug development that activated the field of drug targeting. These approaches can be classified in two major classes: physical-mechanical and biological. In the first class, the concept of controlled and sustained drug release, thus modification of drug concentration-distribution profile by various physical and/or mechanical delivery systems, provided the impetus to attempt drug targeting. The second, the biological type of drug targeting, started with the recognition and the possible use of monoclonal antibodies. Of course, in all these cases of attempted targeting, the active principles were some known drugs. The potential improvement in this direction, modifying drug delivery using the various physical and biological systems, is limited. The selection of the known, marketed drugs in most cases was made considering the best pharmacokinetic (PK)/dynamic profile. Generally, drug researchers selected drugs with an already relatively long duration of action. The improvement, due to controlling drug delivery, thus in general is limited to avoiding high peak concentrations. It should be stressed that research in drug targeting must divert from the classical approaches, that is, to improve some of the known drugs. The design process for drug targeting should be started at a very early stage of the discovery phase. The required properties of a drug that will successfully be involved in the drug targeting, should be different than those of the “classical” drugs. In the foreseeable future, many drugs will be designed with targeting in mind, and the actual new chemical entity will have site specificity and selectivity built into its molecular structure. The pharmaceutical literature of the past 10 to 15 years is very rich in publications on the topic of drug targeting. There are books and proceedings of scientific meetings discussing all the various aspects of this very general and important problem. For example, one review 2 (Tomlison 1987) presented a general approach considering, in a combined form, the disease state and the various delivery parameters including the site of interest, drug retention at the site, duration of the drug effect, the responsiveness of the target tissue, and disposition of the drug. This approach to the problem is very important because in many instances the pathogenesis of the disease was simply ignored in designing drug delivery systems. Developing novel delivery methods, without consideration of disease condition, can lead to meaningless results, and the delivery manipulations will not substantially affect the overall selectivity or efficacy of the drug. The most meaningful classification of drug targeting is mechanism based. Adding one very important class to the two previously mentioned, the three major categories, based on this scheme, can be defined as (1) physical, (2) biological, and (3) chemical (site-specific or targeting systems). The first, physical delivery systems, was reviewed thoroughly in the literature (Friend and

Load more