In Vivo-to-In Vitro Extrapolation of Transporter-Mediated Renal Clearance: Relative Expression Factor Versus Relative Activity Factor Approach.

About 30% of approved drugs are cleared predominantly by renal clearance (CL). Of these, many are secreted by transporters. For these drugs, in vitro-to-in vivo extrapolation of transporter-mediated renal secretory clearance (CL) is important to prospectively predict their renal clearance and to assess the impact of drug-drug interactions and pharmacogenetics on their pharmacokinetics. Here we compared the ability of the relative expression factor (REF) and the relative activity factor (RAF) approaches to quantitatively predict the in vivo CL of 26 organic anion transporter (OAT) substrates assuming that OAT-mediated uptake is the rate-determining step in the CL of the drugs. The REF approach requires protein quantification of each transporter in the tissue (e.g., kidney) and transporter-expressing cells, whereas the RAF approach requires the use of a transporter-selective probe substrate (both in vitro and in vivo) for each transporter of interest. For the REF approach, 50% and 69% of the CL predictions were within 2- and 3-fold of the observed values, respectively; the corresponding values for the RAF approach were 65% and 81%. We found no significant difference between the two approaches in their predictive capability (as measured by accuracy and bias) of the CL or CL of OAT drugs. We recommend that the REF and RAF approaches can be used interchangeably to predict OAT-mediated CL Further research is warranted to evaluate the ability of the REF or RAF approach to predict CL of drugs when uptake is not the rate-determining step. SIGNIFICANCE STATEMENT: This is the first direct comparison of the relative expression factor (REF) and relative activity factor (RAF) approaches to predict transporter-mediated renal clearance (CL). The RAF, but not REF, approach requires transporter-selective probes and that the basolateral uptake is the rate-determining step in the CL of drugs. Given that there is no difference in predictive capability of the REF and RAF approach for organic anion transporter-mediated CL, the REF approach should be explored further to assess its ability to predict CL when basolateral uptake is not the sole rate-determining step.