Follman Kristin E, Dave Rutwij A, Morris Marilyn E
Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, New York, USA.
Biopharm Drug Dispos. 2018 Apr;39(4):218-231. doi: 10.1002/bdd.2128.
Renal impairment (RI) significantly impacts the clearance of drugs through changes in the 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 evaluate quantitatively the effects of renal impairment on the pharmacokinetics of drugs undergoing renal transporter-mediated reabsorption. A previously published semi-mechanistic kidney model incorporating physiologically relevant fluid reabsorption and transporter-mediated active renal reabsorption (PMID: 26341876) was utilized in this study. The probe drug/transporter pair utilized was γ-hydroxybutyric acid (GHB) and monocarboxylate transporter 1 (SCL16A1, MCT1). γ-Hydroxybutyric acid concentrations in the blood and amount excreted into urine were simulated using ADAPT 5 for the i.v. dose range of 200-1500 mg/kg in rats and the impact of renal impairment on CL and AUC was evaluated. A 90% decrease in GFR resulted in a > 100-fold decrease in GHB CL . When expression of reabsorptive transporters was decreased and f was increased, CL approached GFR. The effect of renal impairment on CL was reduced when the expression of drug metabolizing enzymes (DME) was increased as a result of increased metabolic clearance; the converse held true when the 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 renal impairment.
肾功能损害（RI）通过肾小球滤过率的变化、蛋白结合以及肾药物转运蛋白和肝代谢酶表达的改变，对药物清除产生显著影响。本研究的目的是定量评估肾功能损害对经肾转运体介导重吸收的药物药代动力学的影响。本研究使用了先前发表的一个半机制肾脏模型，该模型纳入了生理相关的液体重吸收和转运体介导的主动肾重吸收（ PMID：26341876）。所使用的探针药物/转运体对为γ-羟基丁酸（GHB）和单羧酸转运体1（SCL16A1，MCT1）。使用ADAPT 5模拟大鼠静脉注射剂量范围为200 - 1500 mg/kg时血液中γ-羟基丁酸浓度和尿中排泄量，并评估肾功能损害对CL和AUC的影响。肾小球滤过率降低90%导致GHB的CL降低>100倍。当重吸收转运体的表达降低且f增加时，CL接近肾小球滤过率。当药物代谢酶（DME）的表达因代谢清除增加而增加时，肾功能损害对CL的影响降低；当DME表达降低时，情况则相反。总之，本研究定量证明，肾功能不全对药物清除的影响受转运体表达、肾清除对总清除的贡献、药物代谢酶的表达、游离分数以及与肾转运体抑制剂的药物相互作用（在肾功能损害时可能增加）的调节。
