Effects of renal impairment on transporter‐mediated renal reabsorption of drugs and renal drug–drug interactions: A simulation‐based study

Abstract

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.

Gut-derived uremic toxin handling in vivo requires OAT-mediated tubular secretion in chronic kidney disease

“…shown to mediate the uptake and elimination of a wide range of organic anions, including drugs, endogenous metabolites, signaling molecules, antioxidants, and toxins (including uremic toxins) (14,17,18). In CKD, the expression and function of these transporters has been shown to be altered (64)(65)(66). Using STN in rats as a model of chronic renal failure, we investigated the contribution of the OAT system to residual renal function, with a particular emphasis on the uremic solutes and uremic toxins.…”

Physiologically-Based Pharmacokinetic Modeling for Drug-Drug Interactions of Procainamide and N-Acetylprocainamide with Cimetidine, an Inhibitor of rOCT2 and rMATE1, in Rats

“…Whole-body PBPK models with 11 major tissues were used for the kinetics of PA and NAPA, whereas a minimal PBPK model was used for cimetidine. For kidney, a major organ where DDIs may occur, a previously described semi-mechanistic model was incorporated in the present study [32,33]. Physiological and anatomical variables, required in PBPK calculations, were obtained from the literature [41] (i.e., essentially the default values found in Simcyp software [42], version 15, release 1; Simcyp Limited, Sheffield, UK), as summarized in Table 1.…”

“…In the present study, the semi-mechanistic kidney model [32,33] was incorporated in the PBPK model, based on the considerations of physiologically-relevant fluid reabsorptions and carrier-mediated transports of PA and NAPA (see Appendix A). Briefly, rat kidney was composed of a series of nephron segments (i.e., glomeruli, proximal tubules, loops of Henle, distal tubules, and collecting ducts), in which segmental fluid flow rates and volumes were applied as functions of GFR (Figure 1, Table 1).…”

“…The final model proposed in this study includes the pharmacokinetics of PA and NAPA in major tissue compartments for the prediction of tissue concentrations/urinary excretion profiles as well as plasma concentration profiles in the absence or presence of cimetidine in rats. A series of our simulation studies with the model incorporating semi-mechanistic kidney compartments [32,33] facilitated our sensitivity analysis to determine which process at the level of basolateral uptake by rat organic cation transporter 2 (rOCT2) (i.e., rOCT2, homolog of hOCT2) or apical efflux by rat multidrug and toxin extrusion protein 1 (rMATE1) (i.e., homolog of hMATE1) had more impact on the pharmacokinetics of PA and NAPA.…”

Pharmacokinetic interactions and tolerability of berberine chloride with simvastatin and fenofibrate: an open-label, randomized, parallel study in healthy Chinese subjects

“…Similarly, the absorption of Bbr is significantly decreased when Bbr and baicalin are combined. But the bioavailability of baicalin obviously improved with the presence of Bbr 17. It is well known that CYP3A4 and OATP1BA are metabolic enzymes and transporters, respectively, of Bbr, while baicalin has a significant induction effect on CYP3A4 and OATP1BA, which ultimately leads to the occurrence of drug interactions.…”