抄録
Drug transporters are expressed in many tissues, such as the intestine, liver, kidney, and the brain, and play key roles in drug absorption, distribution and excretion. In this presentation, I will summarize the significant role played by drug transporters in drug disposition, focusing particularly on their roles in the adverse reactions of drugs. The use of transporter function offers the possibility of delivering a drug to the target organ, avoiding distribution to other organs (thereby reducing the chance of toxic side-effects), controlling the elimination process, and/or improving oral bioavailability. It is useful to select a lead compound that may or may not interact with transporters, depending on whether such an interaction is desirable. The expression system of transporters is an efficient tool for screening the activity of individual transport processes. The changes in pharmacokinetics due to genetic polymorphisms and drug-drug interactions involving transporters can often have an adverse effect on the therapeutic safety and efficacy of many important drugs.
For drugs, the target molecule of which is inside the cells, the efflux transporter is the determinant for their pharmacological effect or adverse reactions even though it had negligible impact in the plasma concentrations. Because of difficulty in quantitative evaluation of the subsequent efflux process, the transporters playing key roles in the efflux process remains unclear in humans. Development of probe substrates applicable to the PET imaging will elucidate the quantitative relationship between the transport activities and drug response. Drug transporters are also important for the disposition of endogenous and food derived compounds. Metabonomic analysis has succeeded in identifying such compounds both in animals and human, which could be a good biomarker for the transporter function in vivo.References:
1) Giacomini KM and Sugiyama Y. Membrane transporters and drug response, in “Goodman & Gilman’s The Pharmacological Basis of Therapeutics 12th Edition”, (Brunton LL, Chabner BA, Knollman B, eds) Chapter 5, McGraw-Hill Companies, New York, NY, pp 89-122 (2011).
2) Kusuhara H, Maeda K and Sugiyama Y “Impact of Drug Transporters in the Pharmacological and Adverse Reactions of Drugs” pp563-598 In New Horizons in Predictive Toxicology: Current Status and Application, Ed. by Wilson AGE (2011)
3) Yoshida K, Maeda K, Sugiyama Y. Hepatic and Intestinal Drug Transporters: Prediction of Pharmacokinetic Effects Caused by Drug-Drug Interactions and Ge etic Polymorphisms. Annu Rev Pharmacol Toxicol. 53: 581-612 (2013)
