Comparison of Hepatic Transporter Tissue Expression in Rodents and Interspecies Hepatic OCT1 Activity.
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.
['Morse|Bridget L|BL|', 'Fallon|John K|JK|', 'Kolur|Anil|A|', 'Hogan|Andrew T|AT|', 'Smith|Philip C|PC|', 'Hillgren|Kathleen M|KM|']
D000818:Animals D004285:Dogs D000069347:Erlotinib Hydrochloride D005260:Female D057809:HEK293 Cells D000882:Haplorhini D065669:Hepatobiliary Elimination D022781:Hepatocytes D006801:Humans D007668:Kidney D008099:Liver D008297:Male D008687:Metformin D051379:Mice D018345:Mice, Knockout D027702:Organic Cation Transporter 1 D051381:Rats D055647:Rats, Transgenic D013045:Species Specificity D018170:Sumatriptan D014700:Verapamil
organic anion transporting polypeptide organic cation transporter pharmacokinetics Liver partitioning liver transporters targeted proteomics