Abstract
Organic anion transporters (OATs) play an important role in the renal secretion of drugs, and their functional change can result in pharmacokinetic variability. In this study, we applied transport rates measured using OAT-transfected human embryonic kidney cells to predict human renal secretory and total renal clearance of 31 diverse drugs. Selective substrates to OAT1 (tenofovir), OAT2 (acyclovir and ganciclovir) and OAT3 (benzylpenicillin, oseltamivir acid) were used to obtain relative activity factors (RAFs) for these individual transporters by relating in vitro transport clearance to in vivo secretory clearance. Employing the estimated RAFs - 0.64, 7.3 and 4.1 for OAT1, OAT2 and OAT3, respectively – and the in vitro active clearances, renal secretory clearance and total renal clearance were predicted with an average fold error (AFE) of 1.89 and 1.40, respectively. The results show that OAT3-mediated transport play predominant role in the renal secretion for 22 of 31 drugs evaluated. This mechanistic static approach was further applied to quantitatively predict renal drug-drug interactions (AFE ~1.6) of the substrate drugs with probenecid, a clinical probe OAT inhibitor. In conclusion, the proposed static in vitro-in vivo extrapolation approach is the first comprehensive attempt towards mechanistic modeling of renal secretory clearance based on routinely employed in vitro cell models.
- drug-drug interactions
- in vitro-in vivo prediction (IVIVE)
- kidney/renal
- Transporter-mediated drug/metabolite disposition
- Uptake transporters (OATP, OAT, OCT, PEPT, MCT, NTCP, ASBT, etc.)
- The American Society for Pharmacology and Experimental Therapeutics