Comparison of uptake transporter functions in hepatocytes in different species to determine the optimal model for evaluating drug transporter activities in humans

Abstract

1. A thorough understanding of species-dependent differences in hepatic uptake transporters is critical for predicting human pharmacokinetics (PKs) from preclinical data.

2. In this study, the activities of organic anion transporting polypeptide (OATP/Oatp), organic cation transporter 1 (OCT1/Oct1), and sodium-taurocholate cotransporting polypeptide (NTCP/Ntcp) in cultured rat, dog, monkey and human hepatocytes were compared.

3. The activities of hepatic uptake transporters were evaluated with respect to culture duration, substrate and species-dependent differences in hepatocytes. Longer culture duration reduced hepatic uptake transporter activities across species except for Oatp and Ntcp in rats. Comparable apparent Michaelis–Menten constant (K_m,app) values in hepatocytes were observed across species for atorvastatin, estradiol-17β-glucuronide and metformin. The K_m,app values for rosuvastatin and taurocholate were significantly different across species. Rat hepatocytes exhibited the highest Oatp percentage of uptake transporter-mediated permeation clearance (PS_inf,act) while no difference in %PS_inf,act of probe substrates were observed across species. The in vitro hepatocyte inhibition data in rats, monkeys and humans provided reasonable predictions of in vivo drug–drug interaction (DDIs) between atorvastatin/rosuvastatin and rifampin.

4. These findings suggested that using human hepatocytes with a short culture time is the most robust preclinical model for predicting DDIs for compounds exhibiting active hepatic uptake in humans.

Keywords:

• Species-dependent
• uptake transporters
• hepatocytes

Acknowledgments

We thank Ms Ekta Kadakia for excellent assistance with calculating PK parameters. We also thank Ms Haiyan Xia for technical support and Ms. Rachelle Baker for expert proofreading.

Disclosure statement

The authors declare that there is no conflict of interest regarding the publication of this manuscript.