The Importance of Drug Metabolism Studies for Efficient Drug Discovery and Development.

Abstract

Drug action is the result of interaction with target sites, for both desired (pharmacological) and undesired (toxic) actions, modulated by the transfer processes, the pharmacokinetic variables of absorption, distribution, metabolism and elimination, by which the drug enters and leaves the body. There exist in general better relationships between effect and internal exposure, i.e. target concentrations, most frequently related to plasma concentration, than with the external dose offered. Drug metabolism and pharmacokinetic studies have essential roles to play in all stages of the research and development process, ideally being involved from the pre-nomination phase in drug discovery through to post-marketing surveillance. There occurs far more inter and intraspecies variation, in animals and humans, in the factors influencing the nature and extent of internal exposure, than in the sensitivity of drug targets and this pharmacokinetic variability is the cause of major problems in drug development. The origins of this may be termed “pharmacokinetic defects” and include, inter alia, poor absorption, very short or very long half-life, enzyme induction and high first pass effect. Failure to take these into consideration can cause expensive delay and/or failure during development and make an approved drug vulnerable in the marketplace. It will be argued that the thoughtful inclusion of new feedback loops will improve decision making at various stages during drug development. These should be based on quality metabolic and pharmacokinetic data and exploit the opportunities which the new biology offers for predicting metabolic pathways, anticipating kinetic variability and understanding mechanisms of toxicity. Such improved decision making should contribute to enhanced time- and cost-efficiency of development and ultimately lead to safer, more easily used, drugs.