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 dmd.118.085639
DO 10.1124/dmd.118.085639
A1 Keith A. Riccardi
A1 David A. Tess
A1 Jian Lin
A1 Roshan Patel
A1 Sangwoo Ryu
A1 Karen Atkinson
A1 Li Di
A1 Rui Li
YR 2019
UL http://dmd.aspetjournals.org/content/early/2019/02/20/dmd.118.085639.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 to predict 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. Due to these challenges, a novel unified method has been developed to predict human hepatic clearance for both enzyme- and transporter-mediated mechanisms using cryopreserved suspended human hepatocytes. This method hypothesizes that, once in vitro metabolic stability is scaled by partition coefficients between hepatocytes and buffer with 4% BSA, it can better predict in vivo clearance. With this method, good in vitro - in vivo correlation of human hepatic clearance has been obtained for a set of thirty-two structurally diverse compounds, including transporters such as organic anion-transporting polypeptides 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.