Quantitative Prediction of Human Renal Clearance and Drug-Drug Interactions of Organic Anion Transporter Substrates Using In Vitro Transport Data: A Relative Activity Factor Approach

Abstract

Organic anion transporters (OATs) are important in the renal secretion, and thus, the clearance, of many drugs; and their functional change can result in pharmacokinetic variability. In this study, we applied transport rates measured in vitro 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 (after physiologic scaling) to in vivo secretory clearance. Using the estimated RAFs (0.64, 7.3, and 4.1, respectively, for OAT1, OAT2, and OAT3, respectively) and the in vitro active clearances, renal secretory clearance and total renal clearance were predicted with average fold errors (AFEs) of 1.89 and 1.40, respectively. The results show that OAT3-mediated transport play a predominant role in renal secretion for 22 of the 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 in vitro-in vivo extrapolation approach is the first comprehensive attempt toward mechanistic modeling of renal secretory clearance based on routinely employed in vitro cell models.

Prediction of Transporter‐Mediated Drug‐Drug Interactions for Baricitinib

“…For pemetrexed, a small relative activity factor (RAF) of 5.3 was used, but there were slight differences in methodologies. Others have also reported small RAF values for OAT1 (0.64), OAT2 (7.3), and OAT3 (4.1) …”

Effect of Hepatic Organic Anion‐Transporting Polypeptide 1B Inhibition and Chronic Kidney Disease on the Pharmacokinetics of a Liver‐Targeted Glucokinase Activator: A Model‐Based Evaluation

“…Transport studies using HEK293 cells transfected with renal OATs indicated PF‐04991532 as a substrate to OAT3 but not to OAT1 and OAT2 ( Figure d ). OAT3‐mediated initial uptake clearance was estimated to be ~ 42 μL/minute/10 6 cells from the transfect cell accumulation data using the methodology described by Mathialagan et al …”

“…Transporter‐mediated renal secretion was built into the PBPK model. Uptake clearance via OAT3 was obtained from the rate studies using HEK293‐OATs cells (see RESULTS), as previously described . RAF OAT3 of ~ 4.1, which we previously established based on the in vitro – in vivo extrapolation of OAT3‐mediated transport using static model, was initially applied.…”

“…Uptake clearance via OAT3 was obtained from the rate studies using HEK293‐OATs cells (see RESULTS), as previously described . RAF OAT3 of ~ 4.1, which we previously established based on the in vitro – in vivo extrapolation of OAT3‐mediated transport using static model, was initially applied. This value was further refined (final RAF OAT3 – 3.0) to recover the observed renal clearance and percent amount excretion in urine data from the first‐in‐human studies.…”

“…Transport studies using HEK293 cells transfected with renal OATs indicated PF-04991532 as a substrate to OAT3 but not to OAT1 and OAT2 (Figure 1d). OAT3-mediated initial uptake clearance was estimated to be ~ 42 μL/minute/10 6 cells from the transfect cell accumulation data using the methodology described by Mathialagan et al 14 Finally, PF-04991532, an acidic molecule with pKa of ~ 4.5, showed pH-dependent permeability in Caco-2 cells (a model to assess intestinal absorption). P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor (cyclosporine) and OATP2B1 inhibitors (rifamycin SV and bromosulfophthalein) did not affect the Caco-2 transcellular permeability of PF-04991532 at apical pH of 6.5 and 7.4 ( Figure 1e), suggesting minimal role of active uptake or efflux mechanisms in intestinal permeability.…”