Rifampicin seems to act as both an inducer and an inhibitor of the metabolism of repaglinide
- 410 Downloads
To investigate if rifampicin is both an inducer and an inhibitor of repaglinide metabolism, it was determined whether the timing of rifampicin co-administration influences the pharmacokinetics of repaglinide.
Male volunteers (n=12) participated in a randomised, two-period, crossover trial evaluating the effect of multiple doses of 600 mg rifampicin once daily for 7 days on repaglinide metabolism. Subjects were, after baseline measurements of repaglinide pharmacokinetics, randomised to receive, on either day 7 or day 8 of the rifampicin administration period, a single dose of 4 mg repaglinide and vice versa in the following period.
When repaglinide was given, together with the last rifampicin dose, on day 7, an almost 50% reduction of the median repaglinide area under the plasma concentration–time curve (AUC) was observed. Neither the peak plasma concentration (Cmax), time to reach Cmax (tmax) nor terminal half-life (t1/2) was statistically significantly affected. When repaglinide was given on day 8, 24 h after the last rifampicin dose, an almost 80% reduction of the median repaglinide AUC was observed. The median Cmax was now statistically significantly reduced from 35 ng/ml to 7.5 ng/ml. Neither tmax nor t1/2 was significantly affected.
When rifampicin and repaglinide are administered concomitantly, rifampicin seems to act as both an inducer and an inhibitor of the metabolism of repaglinide. After discontinuing rifampicin administration, while the inductive effect on CYP3A4 and probably also CYP2C8 is still present, an even more marked reduction in the plasma concentration of repaglinide was observed. Our results suggest that concomitant administration of rifampicin and repaglinide may cause a clinically relevant decrease in the glucose-lowering effect of repaglinide, in particular when rifampicin treatment is discontinued or if the drugs are not administered simultaneously or within a few hours of each other.
KeywordsRepaglinide Rifampicin Interaction
Novo Nordisk A/S, Denmark, financed this study. This experiment complies with the current law of the country in which it was performed (Denmark).
- 9.Ged C, Rouillon JM, Pichard L, Combalbert J, Bressot N, Bories P, Michel H, Beaune P, Maurel P (1989) The increase in urinary excretion of 6-beta hydroxycortisol as a marker of human hepatic cytochrome P 450IIIa induction. Br J Clin Pharmacol 28:373–387Google Scholar
- 15.Niemi M, Backman JT, Neuvonen M, Neuvonen PJ (2003) Effects of gemfibrozil, itraconazole, and their combination on the pharmacokinetics and pharmacodynamics of repaglinide: potentially hazardous interaction between gemfibrozil and repaglinide. Diabetologia 46:347–351Google Scholar
- 21.Glaeser H, Drescher S, van der Kuip H, Behrens C, Geick A, Burk O, Dent J, Somogyi A, von Richter O, Griese E, Eichelbaum M, Fromm MF (2002) Shed human enterocytes as a tool for the study of expression and function of intestinal drug-metabolizing enzymes and transporters. Clin Pharmacol Ther 71:131–140CrossRefPubMedGoogle Scholar