薬物動態研究・トランスポーター研究とドラッグデザイン

Abstract

Recently, attempts have been made to synthesize rapidly very large numbers of compounds and identify promising drug candidates in terms of both their pharmacological activity and pharmacokinetic features during the early stages of screening (high throughput screening). In drug development, therefore, the importance of the extrapolation and prediction of pharmacokinetics in humans has increased and physiologically-based pharmacokinetics has played an important role in this.It has become possible to predict in vivo pharmacokinetics in humans if accurate data are available on in vitro drug metabolism, plasma membrane transport, and protein binding and if these data can be combined with physiological parameters such as hepatic blood flow etc. Recent findings are summarized for the quantitative prediction of the hepatic metabolic clearance from in vitro studies using human liver microsomes or P450 isozyme recombinant systems. Furthermore, a method is proposed to predict pharmacokinetic alterations caused by drug-drug interactions based on in vitro metabolic inhibition studies using human liver microsomes or human enzyme expression systems.Biliary or urinary excretion of drugs has been shown to be mediated by various transporters. Some transporters have been shown to be involved also in the efflux of various compounds through the blood-brain barrier (BBB). Examples of the recent studies showing the relevance of transporters in pharmacokinetics are given and the prediction of BBB permeability is also discussed. In future, these transport characteristics of the drug and the possibility of drug-drug interactions involving transport will also need to be taken into consideration for more strategic and efficient drug development.