Effects of Renal Impairment on Transporter-Mediated Renal Reabsorption of Drugs and Renal Drug-Drug Interactions: A Simulation-Based Study

摘要

Renal impairment (RI) significantly impacts the clearance of drugs through changes in glomerular filtration rate, protein binding and alterations in the expression of renal drug transport proteins and hepatic metabolizing enzymes. The objectives of this study were to quantitatively evaluate the effects of RI on the pharmacokinetics of drugs undergoing renal transporter-mediated reabsorption. We utilized a previously published semi-mechanistic kidney model incorporating physiologically-relevant fluid reabsorption and transporter-mediated active renal reabsorption (PMID: 26341876) in this study. The probe drug/ transporter pair utilized was γ-hydroxybutyric acid (GHB) and monocarboxylate transporter 1 (SCL16A1, MCT1). GHB concentrations in the blood and amount excreted into urine were simulated using ADAPT5 for the IV dose range of 200–1500 mg/kg in rats and the impact of RI on CLR and AUC was evaluated. A 90% decrease in GFR resulted in >100-fold decrease in GHB CLR. When expression of reabsorptive transporters was decreased and fu was increased, CLR approached GFR. The effect of RI on CLR was reduced when the expression of drug metabolizing enzymes (DME) was increased as a result of increased metabolic clearance; the converse held true when DME expression was decreased. In conclusion, this study quantitatively demonstrated that the effects of renal insufficiency on the clearance of drugs is modulated by transporter expression, contribution of renal clearance to overall clearance, expression of drug metabolizing enzymes, fraction unbound, and drug-drug interactions with inhibitors of renal transporters that may be increased in the presence of RI.