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ROLE OF PHARMACOKINETICS AND METABOLISM IN DRUG DESIGN
ABSTRACT
Drug discovery and development involve the utilization of in vitro and in vivo experimental models. Different models, ranging from test tube experiments to cell cultures, animals, healthy human subjects, and even small numbers of patients that are involved in clinical trials, are used at different stages of drug discovery and development for determination of efficacy and safety. The proper selection and applications of correct models, as well as appropriate data interpretation, are critically important in decision making and successful advancement of drug candidates. In this review, we discuss strategies in the applications of both in vitro and in vivo experimental models of drug metabolism and disposition.
CHAPTER ONE
1.0 INTRODUCTION
Drug research encompasses several diverse disciplines united by a common goal, namely the development of novel therapeutic agents. The search for drugs can be divided functionally into two stages: Discovery and development. The former consists of setting up a working hypothesis of the target enzyme or receptor for a particular disease, establishing suitable models (or surrogate markers) to test biological activities. Recent surveys indicate that the average new chemical entity taken to market in the united state requires 10 to 15 years of research and costs more than 300 million.
Once the target enzyme or receptor is identified, medicinal chemists use a variety of empirical and semi-empirical structure –activity relationships to modify the chemical structure of a compound to maximize its in vitro activity. However, good in vitro activity cannot be extrapolated to a good in vivo activity unless drug has good bioavailability and a desirable duration of action. A growing awareness of the key roles that pharmacokinetics and drug metabolism play as determinates of in vivo action has led many drug companies to include examination of pharmacokinetics and drug metabolism play as determinants of in vivo drug action has let many drug companies to include examination of pharmacokinetics and drug catabolism properties as part of their screening process in the selection of drug candidates. Consequently industrial drug metabolism scientists here emerged from their traditional supportive role in drug development to provide valuable support in the drug discovery efforts.
To aid in a discovery program, accurate pharmacokinetics and metabolic data must be available almost as early as the results of the in vitro biological screaming. Early pharmacokinetics and metabolic evolution with rapid information feedback is crucial to obtain optimal pharmacokinetics and pharmacological properties. To be effective, the turnover rate needs to be at least three to five compounds per week for the support of each program. Due to time constraints and the availability of only small quantities of each compound in the discovery stay, studies are often limited to one or two animal species. Therefore, the selection of animal species and experimental design of studies are important in providing a reliable prediction of drug absorption and elimination in humans. A good compound could be excluded on the basis of results from an inappropriate animal species or poor experimental design.
After a drug candidate is selected for further development, detailed information on the metabolic processes and pharmacokinetics of the new drug is required by regulating agencies. The rationale for the regulating requirement is best illustrated by the case of active metabolite formation. Many of the currently available psychotropic drugs form one or more metabolites that have their own biological activity (Baldesarini, 1990) pharmacokineticaly, the active metabolites may differ in distribution and clearance from that of the parent drug. pharmacokineticaly, the parent drug and its metabolites may act by similar mechanisms, different mechanisms, are by antagonism. An understanding of the kinetics of active metabolite formation is important not only for predicting therapeutic outcome, but also for explaining the toxicity of specific drugs.
Conventionally, the metabolism of new drugs in humans is studied in vivo using radiotracer techniques as part of clinical absorption and disposition studies. However, this approach often occurs relatively late in the development stage. Ideally, the metabolism of new drugs Should be studied in vitro before the initiation of clinical studies. Early information on in vivo metabolic processes in humans, such as the identification of the enzymes responsible for drug metabolism and scarce design of clinical studies. Early information on in vitro metabolic processes in humans, such as the identification of the enzymes responsible for drug metabolism and scares of potential enzyme polymorphism,those that examine drug-drug interactions. It is also desirable that the comparison for metabolism between animals and humans be performed in the early stage of the drug development process to provide information for the appropriate selection of animal species for toxicity studies before these toxicity studies begin.
The advance of in vitro enzymes used for drug metabolism studies (Wrighton and Stevens.1992), together with the explosion of on knowledge of various dug metabolizing enzymes including undine-diphoshate-glucuronosyl–transsferases (Cougletrie, 1992), cytochromep-450s and carboxylase allows it to obtain early information of the metabolic processes of new drug candidates well before initial clinical studies. In addition, the advent of commercial liquid chromatography mass spectrometry instrumentation and the development of high-field nuclear mantic resonance as well as liquid chromatography–nuclear magnetic resonance technique have further strengthened capability study the metabolism of new drugs in the early drug discovery stage (Baillie and Dave, 1993). However, the race of drug metabolism scientists in drug discovery is more. It really entails a good understanding of the basic mechanisms of the events involved in absorption, distribution, metabolism and excretion, the interaction of decimals with the drug –metabolizing enzymes particularly cytochromep-450s.
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