Towards quantitation of the effects of renal impairment and probenecid inhibition on kidney uptake and efflux transporters, using physiologically based pharmacokinetic modelling and simulations

摘要

Background and Objectives: The kidney is a major drug-eliminating organ. Renal impairment or concomitant use of transporter inhibitors may decrease active secretion and increase exposure to a drug that is a substrate of kidney secretory transporters. However, prediction of the effects of patient factors on kidney transporters remains challenging because of the multiplicity of transporters and the lack of understanding of their abundance and specificity. The objective of this study was to use physiologically based pharmacokinetic (PBPK) modelling to evaluate the effects of patient factors on kidney transporters. Methods: Models for three renally cleared drugs (oseltamivir carboxylate, cidofovir and cefuroxime) were developed using a general PBPK platform, with the contributions of net basolateral uptake transport (T up,b) and apical efflux transport (T eff,a) being specifically defined. Results and Conclusion: We demonstrated the practical use of PBPK models to: (1) define transporter-mediated renal secretion, using plasma and urine data; (2) inform a change in the system-dependent parameter (≥10-fold reduction in the functional 'proximal tubule cells per gram kidney') in severe renal impairment that is responsible for the decreased secretory transport activities of test drugs; (3) derive an in vivo, plasma unbound inhibition constant of T up,b by probenecid (≤1 μM), based on observed drug interaction data; and (4) suggest a plausible mechanism of probenecid preferentially inhibiting T up,b in order to alleviate cidofovir-induced nephrotoxicity.