Cyclosporine markedly raises the plasma concentrations of repaglinide.

Background And Objective: Repaglinide is an antidiabetic drug metabolized by cytochrome P450 (CYP) 2 C 8 and 3A4, and it appears to be a substrate of the hepatic uptake transporter organic anion transporting polypeptide 1B1 (OATP1B1). We studied the effects of cyclosporine (INN, ciclosporin), an inhibitor of CYP3A4 and OATP1B1, on the pharmacokinetics and pharmacodynamics of repaglinide.

Methods: In a randomized crossover study, 12 healthy volunteers took 100 mg cyclosporine or placebo orally at 8 pm on day 1 and at 8 am on day 2. At 9 am on day 2, they ingested a single 0.25-mg dose of repaglinide. Concentrations of plasma and urine repaglinide and its metabolites (M), blood cyclosporine, and blood glucose were measured for 12 hours. The subjects were genotyped for single-nucleotide polymorphisms in CYP2C8, CYP3A5, SLCO1B1 (encoding OATP1B1), and ABCB1 (P-glycoprotein). The effect of cyclosporine on repaglinide metabolism was studied in human liver microsomes in vitro.

Results: During the cyclosporine phase, the mean peak repaglinide plasma concentration was 175% (range, 56%--365%; P=.013) and the total area under the plasma concentration-time curve [AUC0--infinity] was 244% (range, 119%--533%; P<.001) of that in the placebo phase. The amount of unchanged repaglinide and its metabolites M2 and M4 excreted in urine were raised 2.7--fold, 7.5--fold, and 5.0--fold, respectively, by cyclosporine (P<.001). The amount of M1 excreted in urine remained unchanged, but cyclosporine reduced the ratio of M1 to repaglinide by 62% (P<.001). Cyclosporine had no significant effect on the elimination half-life or renal clearance of repaglinide. Although the mean blood glucose-lowering effect of repaglinide was unaffected in this low-dose study with frequent carbohydrate intake, the subject with the greatest pharmacokinetic interaction had the greatest increase in blood glucose-lowering effect. The effect of cyclosporine on repaglinide AUC0-infinity was 42% lower in subjects with the SLCO1B1 521TC genotype than in subjects with the 521TT (reference) genotype (P=.047). In vitro, cyclosporine inhibited the formation of M1 (IC50 [concentration of inhibitor to cause 50% inhibition of original enzyme activity], 0.2 micromol/L) and M2 (IC50, 4.3 micromol/L) but had no effect on M4.

Conclusions: Cyclosporine raised the plasma concentrations of repaglinide, probably by inhibiting its CYP3A4-catalyzed biotransformation and OATP1B1-mediated hepatic uptake. Coadministration of cyclosporine may enhance the blood glucose-lowering effect of repaglinide and increase the risk of hypoglycemia.