ISSX Members are invited to attend a free one-hour webinar on Tuesday, September 27 at 9:00 am ET US.
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.
Even when drugs ultimately undergo metabolism and/or biliary excretion in the liver, their elimination rate is sometimes determined by the hepatic uptake rate mediated by uptake transporters. Elucidation of the rate-determining process in the overall hepatic elimination of drugs is therefore critical for predicting their hepatic clearance, and their systemic and regional exposures. I will show you how to understand the so-called “Extended clearance concept” and to establish a physiologically based pharmacokinetic (PBPK) model that includes the transporter-mediated membrane transport and enzyme-mediated metabolism processes and to investigate the effect of changes in transporter (influx, efflux) function and metabolizing enzyme function on the pharmacokinetics of drugs in the blood and the liver and, ultimately, the pharmacological and/or toxicological effects.
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.
Recently, many studies on genetic polymorphisms (PGx) in drug transporters and transporter-mediated drug-drug interactions(DDI) have been published, and these are part of mechanisms of interindividual difference in drug response. It is important to predict such interindividual difference at early stage of drug development. This presentation will provide a brief overview of extended “clearance concept” and a PBPK model that includes the transporter-mediated transport processes in the liver. With such concept and model, the effect of changes in transporter function on the pharmacokinetics and, ultimately, the pharmacological and/or toxicological effects will be predicted.
- Yoshida K, Maeda K, Sugiyama Y. Hepatic and Intestinal Drug Transporters: Prediction of Pharmacokinetic Effects Caused by Drug-Drug Interactions and Genetic Polymorphisms. Annu Rev Pharmacol Toxicol. 53: 581-612 (2013)
- Yoshikado T, Yoshida K, Kotani N, Nakada T, Asaumi R, Toshimoto K, Maeda K, Kusuhara H,Sugiyama Y. Quantitative Analyses of Hepatic OATP-Mediated Interactions Between Statins and Inhibitors Using PBPK Modeling With a Parameter Optimization Method. Clin Pharmacol Ther. 2016 May 12. doi: 10.1002/cpt.391. [Epub ahead of print] PMID:27170342