Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat.
Bottom Line: This study aimed to define the transporters involved in creatinine secretion, applying that knowledge to establish the mechanism for xenobiotic-induced effects.The basolateral uptake transporters organic anion transporter OAT2 and organic cation transporters OCT2 and OCT3 were found to transport creatinine.Similar to cimetidine and ritonavir, cobicistat had the greatest effect on MATE1 with a 50% inhibition constant of 0.99 μM for creatinine transport.
Affiliation: Gilead Sciences, Foster City, California, USA.
Many xenobiotics including the pharmacoenhancer cobicistat increase serum creatinine by inhibiting its renal active tubular secretion without affecting the glomerular filtration rate. This study aimed to define the transporters involved in creatinine secretion, applying that knowledge to establish the mechanism for xenobiotic-induced effects. The basolateral uptake transporters organic anion transporter OAT2 and organic cation transporters OCT2 and OCT3 were found to transport creatinine. At physiologic creatinine concentrations, the specific activity of OAT2 transport was over twofold higher than OCT2 or OCT3, establishing OAT2 as a likely relevant creatinine transporter and further challenging the traditional view that creatinine is solely transported by a cationic pathway. The apical multidrug and toxin extrusion transporters MATE1 and MATE2-K demonstrated low-affinity and high-capacity transport. All drugs known to affect creatinine inhibited OCT2 and MATE1. Similar to cimetidine and ritonavir, cobicistat had the greatest effect on MATE1 with a 50% inhibition constant of 0.99 μM for creatinine transport. Trimethoprim potently inhibited MATE2-K, whereas dolutegravir preferentially inhibited OCT2. Cimetidine was unique, inhibiting all transporters that interact with creatinine. Thus, the clinical observation of elevated serum creatinine in patients taking cobicistat is likely a result of OCT2 transport, facilitating intracellular accumulation, and MATE1 inhibition.
Mentions: Inhibition of the creatinine transporters identified above by cobicistat and other drugs reported to affect serum creatinine was studied using transfected cell lines and model substrates. Dose–response curves for each transporter are presented in Figure 2, and inhibition constants are summarized in Table 2. All compounds known to affect serum creatinine were found to inhibit OCT2 and MATE1. Similar to cimetidine and ritonavir, cobicistat most potently inhibited MATE1 (half-maximal inhibitory concentration (IC50)=1.87 μmol/l) with a weaker effect on the other transporters. Of the basolateral uptake transporters, cobicistat showed weak inhibition of OCT2 (IC50=24 μmol/l), with little or no inhibition of OCT3 and OAT2 (IC50>100 μmol/l). Dolutegravir was found to be one of the most potent OCT2 inhibitors reported to date based on its effect on tetraethylammonium transport (IC50=0.066 μmol/l). The potent inhibition by dolutegravir was confirmed in a separate assay by the observation of similar inhibition of OCT2-dependent metformin transport (IC50=0.11 μmol/l). These results are consistent with the relatively potent OCT2 inhibition by dolutegravir reported elsewhere.26 Trimethoprim was found to be a relatively potent inhibitor of MATE2-K. Cimetidine was unique in its inhibition of all creatinine transporters.