RT Journal Article SR Electronic T1 Pharmacokinetics of Organic Cation Transporter 1 (OCT1) Substrates in Oct1/2 Knockout Mice and Species Difference in Hepatic OCT1-mediated Uptake JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP dmd.119.088781 DO 10.1124/dmd.119.088781 A1 Bridget L. Morse A1 Anil Kolur A1 Loyd R Hudson A1 Andrew T. Hogan A1 Lisa Hong Chen A1 Ryan M. Brackman A1 Geri A. Sawada A1 John K. Fallon A1 Philip C. Smith A1 Kathleen M. Hillgren YR 2019 UL http://dmd.aspetjournals.org/content/early/2019/11/26/dmd.119.088781.abstract AB Organic Cation Transporter 1 (OCT1) plays a role in hepatic uptake of drugs, affecting in vivo exposure, distinguished primarily through pharmacogenetics of the SLC22A1 gene. The role of OCT1 in vivo has not been confirmed, however, via drug-drug interactions that similarly affect exposure. In the current research we used Oct1/2 knockout mice to assess the role of Oct1 in hepatic clearance and liver partitioning of clinical substrates and assess the knockout model for predicting an effect of OCT1 function on pharmacokinetics in humans. Four OCT1 substrates (sumatriptan, fenoterol, ondansetron, and tropisetron) were administered to wildtype and knockout mice and plasma, tissue and urine collected. Tissue transporter expression was evaluated using LC-MS/MS. In vitro, uptake of all compounds in human and mouse hepatocytes and into human OCT1- and OCT2-expressing cells was evaluated. The largest effect of knockout was on hepatic clearance and liver partitioning of sumatriptan (2 to 5-fold change), followed by fenoterol, while minimal changes in the pharmacokinetics of ondansetron and tropisetron were observed. This aligned with uptake in mouse hepatocytes, in which inhibition of uptake of sumatriptan and fenoterol into mouse hepatocytes by an OCT1 inhibitor was much greater compared to ondansetron and tropisetron. Conversely, inhibition of all four substrates was evident in human hepatocytes, in line with reported clinical pharmacogenetic data. These data confirm the role of Oct1 in the hepatic uptake of the four OCT1 substrates and elucidate species differences in OCT1-mediated hepatocyte uptake that should be considered when utilizing the model to predict effects in humans.SIGNIFICANCE STATEMENT Studies in carriers of SLC22A1 null variants indicate a role of OCT1 in the hepatic uptake of therapeutic agents, although OCT1-mediated drug-drug interactions have not been reported. This work used Oct1/2 knockout mice to confirm the role of Oct1 in the hepatic clearance and liver partitioning in mice for OCT1 substrates with reported pharmacogenetic effects. Species differences observed in mouse and human hepatocyte uptake clarify limitations of the knockout model for predicting exposure changes in humans for some OCT1 substrates.