Rifampicin seems to act as both an inducer and an inhibitor of the metabolism of repaglinide

Eur J Clin Pharmacol. 2004 Apr;60(2):109-14. doi: 10.1007/s00228-004-0746-z. Epub 2004 Mar 19.


Objective: 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.

Methods: 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.

Results: 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 (C(max)), time to reach C(max) (t(max)) nor terminal half-life (t(1/2)) 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 C(max) was now statistically significantly reduced from 35 ng/ml to 7.5 ng/ml. Neither t(max) nor t(1/2) was significantly affected.

Conclusion: 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.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Anti-Bacterial Agents / pharmacology*
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors
  • Aryl Hydrocarbon Hydroxylases / biosynthesis
  • Carbamates / blood
  • Carbamates / pharmacokinetics*
  • Chromatography, High Pressure Liquid
  • Cross-Over Studies
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / biosynthesis
  • Drug Interactions
  • Enzyme Induction
  • Humans
  • Hydrocortisone / analogs & derivatives*
  • Hydrocortisone / urine
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacokinetics*
  • Male
  • Middle Aged
  • Piperidines / blood
  • Piperidines / pharmacokinetics*
  • Quinidine / analogs & derivatives*
  • Quinidine / blood
  • Rifampin / pharmacology*
  • Time Factors


  • Anti-Bacterial Agents
  • Carbamates
  • Cytochrome P-450 Enzyme Inhibitors
  • Hypoglycemic Agents
  • Piperidines
  • 3-hydroxyquinidine
  • 6 beta-hydroxycortisol
  • repaglinide
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • CYP3A protein, human
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Quinidine
  • Rifampin
  • Hydrocortisone