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Comparison of Hepatic Transporter Tissue Expression in Rodents and Interspecies Hepatic OCT1 Activity

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  • Theme: Celebrating Women in the Pharmaceutical Sciences
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Abstract

Hepatic clearance may be uptake rate limited by organic anion transporting polypeptides (OATPs) and organic cation transporter 1 (OCT1). While comparison of OATP activity has been investigated across species, little has been reported for OCT1. Additionally, while data on interspecies transporter expression in the liver exist, quantitative comparison of these transporters in multiple tissues is lacking. In the current research, the pharmacokinetics of OCT1 substrates (sumatriptan and metformin) were assessed in Oct knockout rats for comparison with previous Oct1/2−/− mice data and OCT1 pharmacogenetics in humans. Effect of OCT1 inhibitors verapamil and erlotinib on OCT1 substrate liver partitioning was also evaluated in rats. Expression of 18 transporters, including Oatps and Octs, in 9 tissues from mice and rats was quantitated using nanoLC/MS-MS, along with uptake transporters in hepatocytes from 5 species. Interspecies differences in OCT1 activity were further evaluated via uptake of OCT1 substrates in hepatocytes with corresponding in vivo liver partitioning in rodents and monkey. In Oct1−/− rats, sumatriptan hepatic clearance and liver partitioning decreased; however, metformin pharmacokinetics were unaffected. OCT1 inhibitor coadministration decreased sumatriptan liver partitioning. In rodents, Oatp expression was highest in the liver, although comparable expression of Oatps in other tissues was determined. Expression of Octs was highest in the kidney, with liver Oct1 expression comparably lower than Oatps. Liver partitioning of OCT1 substrates was lower in rodents than in monkey, in agreement with the highest OCT1 expression and uptake of OCT1 substrates in monkey hepatocytes. Species-dependent OCT1 activity requires consideration when translating preclinical data to the clinic.

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Authors and Affiliations

  1. Drug Disposition, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, 46285, USA

    Bridget L. Morse, Anil Kolur, Andrew T. Hogan & Kathleen M. Hillgren

  2. Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    John K. Fallon & Philip C. Smith

Authors
  1. Bridget L. Morse
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  2. John K. Fallon
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  3. Anil Kolur
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  4. Andrew T. Hogan
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Contributions

Bridget L. Morse, Pharm.D./Ph.D., is a Principal Research Scientist in the Drug Disposition Department at Lilly Research Laboratories, Indianapolis, IN. She received her Pharm.D. from Butler University in Indianapolis and her Ph.D. from the University at Buffalo, followed by a postdoctoral fellowship at the University of Western Ontario. Dr. Morse worked in the transporter group within the Department of Metabolism and Pharmacokinetics at Bristol Myers-Squibb for 2 years prior to joining Eli Lilly in 2016. At Lilly, she serves as a subject matter expert in pharmacokinetics, transporters, and drug-drug interactions, particularly in the use of PBPK modeling for hepatic transporter substrates and interspecies translation of hepatic disposition. Dr. Morse has published over 20 journal articles and a chapter on Membrane Drug Transporters in both the 7th and 8th editions of Foye’s Principles of Medicinal Chemistry. She is currently Chair-elect of the AAPS Drug Transporter Community.

Kathleen M. Hillgren, Ph.D., is a Research Fellow in the Drug Disposition Department at Lilly Research Laboratories, Indianapolis, IN. She received her doctorate in Pharmaceutical Chemistry from the University of Kansas and then spent 2 years at the University of California at San Francisco as a postdoctoral fellow. After her fellowship, Dr. Hillgren worked at Rhone-Poulenc Rorer in the Department of Drug Metabolism and Pharmacokinetics where she was responsible for coordinating the preclinical development of drug candidates and in vitro drug absorption models. Dr. Hillgren joined Eli Lilly in 1999. At Lilly, she founded and developed the transporter research group within the Drug Disposition Department, developing assays to study the role of transporters and their pharmacogenomics in the absorption, distribution, and elimination of drugs and metabolites from early discovery through registration. Her research interests include prediction of clinical drug-drug interactions at transporters, transporter pharmacogenomics, and utilization of intestinal transporters for drug delivery. Dr. Hillgren is a charter member and an active participant of the International Transporter Consortium. She is also co-chair of the IQ Consortium’s Transporter Working Group.

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Correspondence to Bridget L. Morse.

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Morse, B.L., Fallon, J.K., Kolur, A. et al. Comparison of Hepatic Transporter Tissue Expression in Rodents and Interspecies Hepatic OCT1 Activity. AAPS J 23, 58 (2021). https://doi.org/10.1208/s12248-021-00583-z

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