RT Journal Article SR Electronic T1 A Novel Unified Approach to Predict Human Hepatic Clearance for Both Enzyme- and Transporter-Mediated Mechanisms Using Suspended Human Hepatocytes JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 484 OP 492 DO 10.1124/dmd.118.085639 VO 47 IS 5 A1 Riccardi, Keith A. A1 Tess, David A. A1 Lin, Jian A1 Patel, Roshan A1 Ryu, Sangwoo A1 Atkinson, Karen A1 Di, Li A1 Li, Rui YR 2019 UL http://dmd.aspetjournals.org/content/47/5/484.abstract AB The accurate prediction of human pharmacokinetics is critically important in modern drug discovery since it drives both pharmacological and toxicological effects. Although significant progress has been made in predicting drug disposition by hepatic drug–metabolizing enzymes, predicting transporter-mediated clearance is still highly uncertain. Furthermore, different approaches are often used to predict clearance with and without transporter involvement, hence the major clearance pathway for a compound must first be determined to know which approach to use. As a result of these challenges, a novel unified method has been developed using cryopreserved suspended human hepatocytes to predict human hepatic clearance for both enzyme- and transporter-mediated mechanisms. This method hypothesizes that, once in vitro metabolic stability is scaled by partition coefficients between hepatocytes and buffer with 4% bovine serum albumin, in vivo clearance can be better predicted. With this method, good in vitro–in vivo correlation of human hepatic clearance has been obtained for a set of 32 structurally diverse compounds, including such transporters as organic anion–transporting polypeptide substrates. The clearance predictions for most compounds are within 3-fold of observed values. This is the first time that multiple compounds result in good in vitro–in vivo extrapolation using an entirely “bottom-up” approach without any empirical scaling factor when transporter-mediated clearance is involved. Potential exceptions are compounds with significant biliary and/or extra-hepatic clearance. The method offers an alternative approach to more accurately predict human hepatic clearance when multiple complex mechanisms are involved.