%0 Journal Article %A Emi Kimoto %A Sumathy Mathialagan %A Laurie Tylaska %A Mark Niosi %A Jian Lin %A Anthony A Carlo %A David A Tess %A Manthena V. S. Varma %T Organic Anion Transporter 2 mediated Hepatic Uptake Contribute to the Clearance of High Permeability - Low Molecular Weight Acid and Zwitterion Drugs: Evaluation using 25 drugs. %D 2018 %R 10.1124/jpet.118.252049 %J Journal of Pharmacology and Experimental Therapeutics %P jpet.118.252049 %X High permeability-low molecular weight acids/zwitterions (i.e., extended clearance classification system class 1A, ECCS 1A drugs) are considered to be cleared by metabolism with minimal role of membrane transporters in their hepatic clearance. However, marked disconnect in the in vitro - in vivo (IVIV) translation of hepatic clearance is often noted for these drugs; wherein, metabolic rates measured using human liver microsomes and primary hepatocytes tend to underpredict. Here, we evaluated the role of organic anion transporter 2 (OAT2)-mediated hepatic uptake in the clearance of ECCS 1A drugs. To this end, for a set of 25 ECCS 1A drugs, in vitro transport activity was assessed using transporter-transfected cells and primary human hepatocytes. All but 2 drugs showed substrate affinity to OAT2, while 4 (bromfenac, entacapone, fluorescein and nateglinide) also showed OATP1B1 activity in transfected cells. The majority of these drugs (21 of 25) showed active uptake by plated human hepatocytes, with rifamycin SV (pan-transporter inhibitor) reducing the uptake by about 25-95%. Metabolic turnover was estimated for 19 drugs, after a few showed no measurable substrate depletion, in liver microsomal incubations containing cofactors of both oxidative and glucuronidation pathways. IVIV extrapolation using in vitro data was evaluated to project human hepatic clearance of OAT2-alone substrates considering (i) uptake transport only (ii) metabolism only, and (iii) transporter-enzyme interplay (extended clearance model). The transporter-enzyme interplay approach achieved improved prediction accuracy (average fold error =1.9 and bias =0.93) compared to other 2 approaches. In conclusion, this study provides functional evidence for the role of OAT2-mediated hepatic uptake in determining the pharmacokinetics of several clinically important ECCS 1A drugs. %U https://jpet.aspetjournals.org/content/jpet/early/2018/08/22/jpet.118.252049.full.pdf