Evaluation of the Potency of Telaprevir and Its Metabolites as Inhibitors of Renal Organic Cation Transporters, a Potential Mechanism for the Elevation of Serum Creatinine

Abstract

Telaprevir-based triple therapy is a highly effective treatment for chronic hepatitis C. However, adverse reactions include reversible and dose-dependent elevation of serum creatinine levels. We speculated that this effect reflects inhibition of the renal organic cation transporters hOCT2, hMATE1, and hMATE2-K by telaprevir or its metabolites (VRT-127394 and VRT-0922061). Telaprevir, VRT-127394, and VRT-0922061 showed negligible or weak effects on hOCT2 at concentrations of ≥20 µM, but inhibited hMATE1 by 35, 38, and 53% and hMATE2-K by 47, 45, and 61% at 100 µM, respectively. Telaprevir or its metabolites (10 µM) did not affect basal-to-apical transport of MPP(+) across monolayers of hOCT2-hMATE1 double-transfected MDCKII cells, whereas pyrimethamine, a potent inhibitor of hMATE1, markedly inhibited MPP(+) transport. Taken together, inhibition of hOCT2, hMATE1, and hMATE2-K is unlikely to be clinically relevant because unbound plasma concentrations of telaprevir and its metabolites reach only 2 µM following oral administration of a dose of 750 mg telaprevir. Hence, elevated serum creatinine during telaprevir therapy may not be related to direct inhibition of renal organic cation transporters.

Does elevation of serum creatinine in patients with chronic hepatitis C under therapy of telaprevir mean renal impairment?

“…However, Nakada et al . revealed that TVR did not inhibit OCT2 at clinically relevant concentrations . This result is not consistent with those reported by Kunze et al .…”

“…MATE is also considered to mediate directional transport of creatinine across proximal tubules. 17,18 These studies indicate that TVR inhibits OCT2 and MATE, leading to a decrease in tubular secretion of creatinine and therefore an increase in the SCr concentration. However, Nakada et al revealed that TVR did not inhibit OCT2 at clinically relevant concentrations.…”

“…showed that OCT2 was the only transporter mediating creatinine transport among several organic ion transporters and was responsible for regulating creatinine uptake at the basolateral membranes of renal proximal tubules. MATE is also considered to mediate directional transport of creatinine across proximal tubules . These studies indicate that TVR inhibits OCT2 and MATE, leading to a decrease in tubular secretion of creatinine and therefore an increase in the SCr concentration.…”

“…The reason for this discrepancy remains unknown. On the other hand, both reports demonstrated that TVR inhibited MATE . Kusuhara et al .…”

Telaprevir-Induced Renal Adverse Events in Japanese Patients Reported in the PMDA Adverse Drug Reactions Reporting Database

“…However, Nakada et al concluded that elevated serum creatinine during telaprevir therapy may not be related to the direct inhibition of renal organic cation transporters. 17 In addition, increase of creatinine levels was not reported in clinical trials of telaprevir. Loustaud-Ratti et al suggested that unpredictable renal toxicity might occur during therapy in addition to OCT2 inhibition.…”