Functional characterization for polymorphic organic anion transporting polypeptides (OATP/SLCO1B1, 1B3, 2B1) of monkeys recombinantly expressed with various OATP probes

Abstract

The hepatic uptake of clinical drugs mediated by human hepatic organic anion transporting polypeptides (OATP/SLCO) has been reported extensively. In this study, hepatic uptake by recombinantly expressed monkey OATP1B1, OATP1B3 and OATP2B1 was investigated using three human OATP1B1 and OATP1B3 substrates (pitavastatin, pravastatin and rosuvastatin) and one OATP1B3 substrate (telmisartan), as the governmental drug interaction guidelines recommend, and seven reported clinical drugs. The uptake of known human probes into recombinant OATP-expressing cells was significantly greater than that of mock cells. Consequently, pitavastatin, pravastatin and rosuvastatin were suggested to be substrates of recombinant monkey OATP1B1 and OATP1B3, and telmisartan was suggested to be a substrate of recombinant monkey OATP1B3, in a manner similar to human OATPs. In contrast, atorvastatin, bosentan, etoposide, fexofenadine, fluvastatin, glibenclamide and simeprevir were broadly transported by recombinant monkey OATP1B1, OATP1B3 and OATP2B1. Furthermore, some of the 16 non-synonymous monkey OATP1B1 variants found in 64 cynomolgus and 32 rhesus monkeys mediated up to a 1.6-fold [³ H]pitavastatin uptake (with low Michaelis constant values) in comparison with the wild type under the present conditions. Despite sequences of monkey recombinant OATPs not being totally reflective of those of human OATPs, our results collectively suggested that OATP1B1, OATP1B3 or OATP2B1 in monkeys could mediate roughly a similar hepatic uptake of various OATP probes. Recombinant monkey OATPs would be good experimental tools for in vitro hepatic uptake in cell systems.

Keywords: genetic polymorphisms; monkey OATP; pitavastatin; telmisartan.