Abstract
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 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 with you how to understand the so-called "Extended clearance concept (ECC)" (1) and to establish a physiologically based pharmacokinetic (PBPK) model (2) that includes that the passive transport and transporter-mediated membrane transport and enzyme-mediated metabolism processes. I will also share with you how to investigate the effect of changes in transporter function and metabolizing enzyme function on the pharmacokinetics of drugs in the blood and the liver and, ultimately, the pharmacological and/or toxicological effect. Most recently, ECC has been used by a few pharmaceutical industries to predict the predominant clearance mechanism based on physicochemical properties and this may aid in selecting the appropriate preclinical studies for optimizing the drug exposure.
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.
This study proposed a method to optimize in vivo PBPK parameters in hepatic uptake/efflux/enzyme transporter-mediated DDIs based on several important drug dependent in vitro parameters on transport, metabolism and inhibition(2).
[References]
1) Giacomini KM and Sugiyama Y. Membrane transporters and drug response, in "Goodman & Gilman's The Pharmacological Basis of Therapeutics 13th Edition", (Brunton LL, Dandan RH, Knollman B, eds) Chapter 5, Section 1, McGraw-Hill Companies, New York, NY, pp 65-84 (2018).
2) 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)
