| contraindicació de l'ús concomitant de repaglinida i gemfibrozil |
| © Springer-Verlag 2003 Rapid Communication Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide M. Niemi1, J. T. Backman1, M. Neuvonen1 and P. J. Neuvonen1 (1) Department of Clinical Pharmacology, Helsinki University Central Hospital, P.O. Box 340, 00029, HUS, Finland 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 (t1/2) 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 t1/2 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. Keywords CYP2C8 - CYP3A4 - drug interaction - gemfibrozil - hypoglycaemia - itraconazole - repaglinide Abbreviations AUC area under the concentration-time curve from time zero to infinity AUC0–7 area under the concentration-time curve from time zero to 7 h AUC0–8 area under the concentration-time curve from time zero to 8 h C7 concentration at 7 h Cmax peak concentration CYP cytochrome P450 tmax time to peak concentration t1/2 elimination half-life |