Impact of Hepatic Uptake Transporters on Pharmacokinetics and Drug-Drug Interactions: Use of Assays and Models for Decision Making in the Pharmaceutical Industry Mathew G. Soars, Peter J. H. Webborn, and Robert J. Riley* Department of DiscoVery DMPK, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K. Received November 27, 2008; Revised Manuscript Received April 27, 2009; Accepted April 29, 2009 Abstract: The ability to predict hepatic metabolic clearance is a key component in the design and selection of small molecule drug candidates within the pharmaceutical industry. The recognition that metabolism-transporter interplay can influence hepatic metabolic clearance has presented new challenges, both in terms of the creation of experimental systems suitable for an industry setting and also in developing an understanding of the pharmacokinetic concepts that underpin them. This paper reviews the pharmacokinetic principles that govern the kinetics of uptake transporter substrates. In addition, new data are presented from a range of test systems for assessing hepatic drug clearance and the impact of drug-drug interactions (DDIs). Keywords: Transporter; hepatic; prediction; uptake; OATP1B1; modeling; review; hepatocytes 1. Introduction The liver is known to play a key role in drug elimination through both metabolism and the transporter-mediated secre- tion of drugs and/or metabolites into bile. An additional level of complexity was introduced when it was established that transporter-mediated uptake of drug from plasma could influence the overall rate of elimination. 1,2 This was most clearly observed for pravastatin, a compound eliminated predominantly via biliary secretion, for which hepatic uptake was shown to be the rate-determining step in its elimination in the rat. 3 Clearly there is interplay between these processes, with transporters either delivering compounds to, or removing compounds from, the site of metabolism 4 or biliary secretion. One measure of the level of understanding of complex biological processes is the ability to accurately predict in vivo behavior from in vitro data. Understanding is encap- sulated in the mathematical models used to integrate the in vitro parameters and link them quantitatively to their in vivo counterparts. Potentially a more important reflection of this understanding is the selection of appropriate in vitro experi- mental test systems and description of their capabilities and limitations. Prediction of hepatic clearance from a variety of in vitro systems has formed a cornerstone of the design and selection of small molecule drug candidates within the pharmaceutical industry for more than a decade. For compounds whose clearance is predominantly via hepatic metabolism the approaches taken have been relatively successful, 5-9 al- though not without their failures. 9,10 The realization that hepatic transporters may add additional layers of complexity * Corresponding author: Dr R J Riley, Department of Discovery DMPK, AstraZeneca R&D Charnwood, Bakewell Road, Loughborough, Leicestershire LE11 5RH, U.K. E-mail: rob.riley@astrazeneca.com. Phone: +44 (0)1509 64 4039. Fax: +44 (0)1509 64 5576. (1) Mizuno, N.; Niwa, T.; Yotsumoto, Y.; Sugiyama, Y. Impact of drug transporter studies on drug discovery and drug development. Pharmacol. ReV. 2003, 55, 425–461. (2) Shitara, Y.; Horie, T.; Sugiyama, Y. Transporters as a determinant of drug clearance and tissue distribution. Eur. J. Pharam. Sci. 2006, 27, 425–446. (3) Yamazaki, M.; Tokui, T.; Ishigami, M.; Sugiyama, Y. Tissue- selective uptake of pravastatin in rats: contribution of a specific carrier-mediated uptake system. Biopharm. Drug Dispos. 1996, 17, 775–789. (4) Benet, L. Z.; Cummins, C. L.; Wu, C. Unmasking the dynamic interplay between efflux transporters and metabolic enzymes. Int. J. Pharm. 2004, 277, 3–9. (5) Soars, M. G.; Burchell, B.; Riley, R. J. In Vitro analysis of human drug glucuronidation and prediction of in vivo metabolic clearance. J. Pharmacol. Exp. Ther. 2002, 301, 382–390. reviews 1662 MOLECULAR PHARMACEUTICS VOL. 6, NO. 6, 1662–1677 10.1021/mp800246x CCC: $40.75  2009 American Chemical Society Published on Web 04/29/2009