Organic anion transporting polypeptide (OATP1B) plays a key role in the hepatic clearance of a majority of high molecular weight (MW) acids and zwitterions. Here, we evaluated the role of OATP1B-mediated uptake in the clearance of novel hypoxia-inducible factor prolyl hydroxylase inhibitors (“dustats”), which are typically low MW (300–400 Da) aliphatic carboxylic acids. Five acid dustats, namely daprodustat, desidustat, enarodustat, roxadustat, and vadadustat, showed specific transport by OATP1B1/1B3 in transporter-transfected HEK293 cells. Neutral compound, molidustat, was not a substrate to OATP1B1/1B3. None of the dustats showed transport by other hepatic uptake transporters, including NTCP, OAT2, and OAT7. In the primary human hepatocytes, uptake of all acids was significantly reduced by rifampin (OATP1B inhibitor), with an estimated fraction transported by OATP1B (ft,OATP1B) of up to >80% (daprodustat). Molidustat uptake was minimally inhibited by rifampin; and low permeability acids (desidustat and enarodustat) also showed biliary efflux in sandwich culture human hepatocytes. In vivo, intravenous pharmacokinetics of all five acids was significantly altered by a single-dose rifampin (30 mg/kg) in Cynomolgus monkey. Hepatic clearance (nonrenal) was ∼4-fold (vadadustat) to >11-fold (daprodustat and roxadustat) higher in control group compared with rifampin-treated subjects. In vivo ft,OATP1B was estimated to be ∼70%–90%. In the case of molidustat, rifampin had a minimal effect on overall clearance. Rifampin also considerably reduced volume of distribution of daprodustat and roxadustat. Overall, OATP1B significantly contribute to the hepatic clearance and pharmacokinetics of several dustats, which are low MW carboxylic acids. OATP1B activity should therefore by evaluated in this property space.

SIGNIFICANCE STATEMENT The in vitro and in vivo results of this study suggest that organic anion transporting polypeptide (OATP1B)-mediated hepatic uptake play a significant role in the pharmacokinetics of low molecular weight (MW) acidic dustats, which are being developed or are approved for the treatment of anemia in chronic kidney disease. Significant active uptake mechanisms are not apparent for the neutral compound, molidustat. Characterization of uptake mechanisms is therefore important in predicting human pharmacokinetics and evaluating drug-drug interactions for low MW acids.

All authors are full-time employees of Pfizer Inc. at the time of this study. Authors declare no conflicts of interest that are directly relevant to this study.

dx.doi.org/10.1124/dmd.123.001630.

↵This article has supplemental material available at dmd.aspetjournals.org.