Abstract

Organic anion transporting polypeptide (OATP) 1B1 and 1B3 are key molecules that are involved in hepatic uptake related to drug elimination, and OATP-mediated drug interactions are of clinical concern. In this study, with an aim to determine a cutoff value for the potential involvement of OATP, we collected data on the distribution of 12 human OATP and 24 non-OATP radiolabeled substrates in rats. The OATP substrates exhibited a higher tissue-to-plasma ratio (K_p) in the liver than that in the other tissues. As an index of liver-specific distribution, a hepatic K_p ratio (the ratio of K_p in the liver to that in other tissues) was introduced, and a hepatic K_p ratio <10 was proposed as a criterion for excluding the involvement of OATP in vivo. Approximately 20% of the non-OATP substrates as well as 100% of the OATP substrates exceeded the cutoff value of 10; therefore, further in vitrotransport studies will be required to decide whether to conduct clinical drug interaction studies. Since distribution studies are usually conducted in rats during drug development, the use of a hepatic K_p ratio is practical and could refine the current decision tree for selecting OATP substrates in the drug interaction guidance/guidelines.