Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide

Abstract

Aims/hypothesis. Our aim was to investigate possible interactions of gemfibrozil, itraconazole, and their combination with repaglinide. Methods. In a randomised crossover study, 12 healthy volunteers received twice daily for 3 days either 600 mg gemfibrozil, 100 mg itraconazole (first dose 200 mg), both gemfibrozil and itraconazole, or placebo. On day 3 they ingested a 0.25 mg dose of repaglinide. Plasma drug and blood glucose concentrations were followed for 7 h and serum insulin and C-peptide concentrations for 3 h postdose. Results. Gemfibrozil raised the area under the plasma concentration-time curve (AUC) of repaglinide 8.1-fold (range 5.5-to 15.0-fold; p<0.001) and prolonged its half-life (t 1/2 ) from 1.3 to 3.7 h (p<0.001). Although itraconazole alone raised repaglinide AUC only 1.4-fold (1.1-to 1.9-fold; p<0.001), the gemfibrozil-itraconazole combination raised it 19.4-fold (12.9-to 24.7-fold) and prolonged the t 1/2 of repaglinide to 6.1 h (p<0.001). Plasma repaglinide concentration at 7 h was increased 28.6-fold by gemfibrozil and 70.4-fold by the gemfibrozil-itraconazole combination (p<0.001). Gemfibrozil alone and in combination with itraconazole considerably enhanced and prolonged the blood glucose-lowering effect of repaglinide; i.e., repaglinide became a long-acting and stronger antidiabetic. Conclusion/interpretation. Clinicians should be aware of this previously unrecognised and potentially hazardous interaction between gemfibrozil and repaglinide. Concomitant use of gemfibrozil and repaglinide is best avoided. If the combination is considered necessary, repaglinide dosage should be greatly reduced and blood glucose concentrations carefully monitored. [Diabetologia (2003) 46:347-351] Keywords CYP2C8, CYP3A4, drug interaction, gemfibrozil, hypoglycaemia, itraconazole, repaglinide. Corresponding author: P. J. Neuvonen, Department of Clinical Pharmacology, Helsinki University Central Hospital, P.O. Box 340, 00029, HUS, Finland E-mail: pertti.neuvonen@hus.fi Abbreviations: AUC, area under the concentration-time curve from time zero to infinity; AUC 0-7 , area under the concentration-time curve from time zero to 7 h; AUC 0-8 , area under the concentration-time curve from time zero to 8 h; C 7 , concentration at 7 h; C max , peak concentration; CYP, cytochrome P450; t max , time to peak concentration; t 1/2 , elimination halflife.

Drug Interactions of Medications Commonly Used in Diabetes

“…In vivo, gemfibrozil increases the total exposure of repaglinide eightfold. 21 Several reports of severe, prolonged hypoglycemia have been documented with the combination. 22 Strong inhibitors of CYP3A4, such as azole antifungal agents and erythromycin derivatives, may also enhance the hypoglycemic effect of repaglinide.…”

Changes in the Pharmacokinetics of Rosiglitazone, a CYP2C8 Substrate, When Co-Administered with Amlodipine in Rats

“…It is mainly metabolized via N-methylation and para-hydroxylation by CYP2C8 through phase I metabolism, and to a lesser extent by CYP2C9 (Baldwin et al, 1999). Recently, the contributions made by CYP2C8 to the metabolisms of cerivastatin, paclitaxel, repaglinide, and verapamil have been studied Tracy et al, 1999;Mück, 2000;Niemi et al, 2003a). The pharmacokinetics of rosiglitazone is known to be altered when it is co-administered with other drugs which were involved with the induction or inhibition of CYP2C8, such as, gemfibrozil, trimethoprim and rifampin (Tracy et al, 1999;Park et al, 2004;Hruska et al, 2005).…”

Pharmacokinetic Interaction between Nisoldipine and Repaglinide in Rats

“…These results are consistent with a report by Niemi et al (2001) showing that clarithromycin, a CYP3A4 inhibitor, signifi cantly increased the AUC 0−∞ and C max of repaglinide. Niemi et al (2003) reported that gemfi brozil signifi cantly increased the AUC 0−∞ of repaglinide 8.1-fold, while Kajosaari et al (2005) also reported that co-administration of repaglinide with the known P-gp inhibitor cyclosporine A signifi cantly increased the plasma concentration of repaglinide in humans.…”