Cyclosporine A Increases Plasma Concentrations and Effects of Repaglinide

Abstract

To the Editor: We read with interest the article by Türk et al. titled 'Repaglinide in the Management of New-Onset Diabetes Mellitus After Renal Transplantation' (1Türk T Pietruck F Dolff S et al.Repaglinide in the management of new-onset diabetes mellitus after renal transplantation..Am J Transplant. 2006; 6: 842-846Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). While we agree with the conclusions of this observational study that repaglinide can be effective in the treatment of new-onset diabetes mellitus (NODM) after renal transplantation, we are concerned about the risk of interaction between cyclosporine A and repaglinide. In their discussion, the authors suggest that relevant changes in repaglinide concentrations due to interactions with calcineurin inhibitors are unlikely to occur (1Türk T Pietruck F Dolff S et al.Repaglinide in the management of new-onset diabetes mellitus after renal transplantation..Am J Transplant. 2006; 6: 842-846Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). This suggestion is based on the dual metabolism of repaglinide by the cytochrome P450 (CYP) 2C8 and 3A4 isoenzymes, which are proposed to be able to compensate for each other if the other isoenzyme is inhibited (2Bidstrup TB Bjørnsdottir I Sidelmann UG Thomsen MS Hansen KT CYP2C8 and CYP3A4 are the principal enzymes involved in the human in vitro biotransformation of the insulin secretagogue repaglinide..Br J Clin Pharmacol. 2003; 56: 305-314Crossref PubMed Scopus (173) Google Scholar). However, the fibric acid derivative gemfibrozil increases the area under the plasma concentration-time curve (AUC) of repaglinide (reflecting total exposure to repaglinide) almost 10-fold (3Niemi M Backman JT Neuvonen M Neuvonen PJ Effects of gemfibrozil,itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: Potentially hazardous interaction between gemfibrozil and repaglinide..Diabetologia. 2003; 46: 347-351Crossref PubMed Scopus (241) Google Scholar), indicating that the dual metabolism of repaglinide does not eliminate the risk of interaction. Moreover, our recent results demonstrate that cyclosporine A markedly raises the plasma concentrations of repaglinide (4Kajosaari LI Niemi M Neuvonen M Laitila J Neuvonen PJ Backman JT Cyclosporine markedly raises the plasma concentrations of repaglinide..Clin Pharmacol Ther. 2005; 78: 388-399Crossref PubMed Scopus (177) Google Scholar). In the cross-over study in healthy adults, cyclosporine A (100 mg, ingested 13 h and 1 h before repaglinide) increased the peak plasma concentration of repaglinide 1.8-fold and its AUC 2.4-fold (4Kajosaari LI Niemi M Neuvonen M Laitila J Neuvonen PJ Backman JT Cyclosporine markedly raises the plasma concentrations of repaglinide..Clin Pharmacol Ther. 2005; 78: 388-399Crossref PubMed Scopus (177) Google Scholar). The extent of the interaction showed considerable interindividual variability (e.g. a 5.3-fold increase in repaglinide exposure was observed in one of the 12 subjects), which is, at least partially, due to genetic factors. Because the effects of cyclosporine A are dependent on its concentrations, the extent of this interaction can be greater in patients receiving continuous immunosuppression with cyclosporine A than in the study with a relatively small dose of cyclosporine A. A likely explanation for this interaction is the dual inhibitory effect of cyclosporine A on the CYP3A4-catalyzed biotransformation and active transporter-mediated uptake of repaglinide into hepatocytes. In addition to the well-known inhibitory effects of cyclosporine A on CYP3A4 and P-glycoprotein, cyclosporine A is a potent inhibitor of the hepatic uptake transporter OATP1B1 (previously known as LST-1, OATP2 or OATP-C) (5Shitara Y Itoh T Sato H Li AP Sugiyama Y Inhibition of transportermediated hepatic uptake as a mechanism for drug-drug interaction between cerivastatin and cyclosporin A..J Pharmacol Exp Ther. 2003; 304: 610-616Crossref PubMed Scopus (314) Google Scholar). Inhibition of this transporter partially explains the effects of cyclosporine A on the pharmacokinetics of other drugs, including repaglinide and several statins. Also gemfibrozil has a dual inhibitory effect, which explains its strong interaction with repaglinide: it inhibits both CYP2C8 and OATP1B1 (6Shitara Y Hirano M Sato H Sugiyama Y Gemfibrozil and its glucuronide inhibit the organic anion transporting polypeptide2 (OATP2/OATP1B1:SLC21A6)-mediated hepatic uptake and CYP2C8-mediated metabolism of cerivastatin: Analysis of the mechanism of the clinically relevant drug-drug interaction between cerivastatin and gemfibrozil..J Pharmacol Exp Ther. 2004; 311: 228-236Crossref PubMed Scopus (373) Google Scholar). The interaction between cyclosporine A and repaglinide is of clinical significance; it can increase the glucose-lowering efficacy of repaglinide, but it can also lead to an elevated risk of hypoglycemia. In the study of Türk et al., a successful blood glucose response to repaglinide was obtained in 86% of patients on cyclosporine A, while less than 60% of the other patients responded successfully to repaglinide (1Türk T Pietruck F Dolff S et al.Repaglinide in the management of new-onset diabetes mellitus after renal transplantation..Am J Transplant. 2006; 6: 842-846Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). It is possible that the good response to repaglinide in cyclosporine A-treated patients was due to the pharmacokinetic interaction between these two agents. Moreover, Trk et al. report that three patients reported symptoms of a hypoglycemic episode during treatment with repaglinide (1Türk T Pietruck F Dolff S et al.Repaglinide in the management of new-onset diabetes mellitus after renal transplantation..Am J Transplant. 2006; 6: 842-846Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar). It would be pertinent to know if these patients were also treated with cyclosporine A. To conclude, cyclosporine A can markedly increase the plasma concentrations of repaglinide. Their concomitant use may enhance the blood glucose-lowering effect of repaglinide, but this positive effect is associated with an increased risk of hypoglycemia. Therefore, care is warranted when using repaglinide in patients receiving cyclosporine A immunosuppression.