Pioglitazone, an in vitro inhibitor of CYP2C8 and CYP3A4, does not increase the plasma concentrations of the CYP2C8 and CYP3A4 substrate repaglinide

Eur J Clin Pharmacol. 2006 Mar;62(3):217-23. doi: 10.1007/s00228-005-0093-8. Epub 2006 Jan 31.


Objective: Pioglitazone, a thiazolidinedione antidiabetic, inhibits cytochrome P450 (CYP) 2C8 and CYP3A4 enzymes in vitro. Repaglinide, a meglitinide analogue antidiabetic, is metabolised by CYP2C8 and CYP3A4. In patients with type 2 diabetes, the pioglitazone-repaglinide combination has acted synergistically on glycaemic parameters. Our aim was to determine whether pioglitazone increases the plasma concentrations of repaglinide.

Methods: In a randomized, 2-phase cross-over study, 12 healthy volunteers received 30 mg pioglitazone or placebo once daily for 5 days. On day 5, they ingested a single 0.25 mg dose of repaglinide 1 h after the last pretreatment dose. Plasma repaglinide and pioglitazone, and blood glucose concentrations were measured for 12 h.

Results: During the pioglitazone phase, the mean peak plasma repaglinide concentration (C(max)) and the total area under the concentration-time curve [AUC(0-infinity)] of repaglinide were 100% (range 53-157%, P=0.99) and 90% (range 63-120%, P=0.22), respectively, of those during the placebo phase. Also the half-life of repaglinide was unaffected, but the median peak time of repaglinide was shortened from 40 min to 20 min by pioglitazone (P=0.014). The short-term pioglitazone administration did not modify the blood glucose-lowering effect of a single dose of repaglinide.

Conclusions: Pioglitazone does not increase the plasma concentrations of repaglinide, indicating that the inhibitory effect of pioglitazone on CYP2C8 and CYP3A4 is very weak in vivo, probably due to its extensive plasma protein binding. The synergistic effect of repaglinide and pioglitazone on the glycaemic parameters, seen in patients with type 2 diabetes during their long-term use, is unlikely to be caused by inhibition of repaglinide metabolism by pioglitazone.

Publication types

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

MeSH terms

  • Administration, Oral
  • Adult
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / antagonists & inhibitors*
  • Aryl Hydrocarbon Hydroxylases / metabolism
  • Blood Glucose / metabolism
  • Capsules
  • Carbamates / blood
  • Carbamates / metabolism
  • Chromatography, Liquid / methods
  • Cross-Over Studies
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors*
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Administration Schedule
  • Enzyme Inhibitors / blood
  • Enzyme Inhibitors / pharmacokinetics
  • Female
  • Gas Chromatography-Mass Spectrometry / methods
  • Half-Life
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / blood
  • Hypoglycemic Agents / pharmacokinetics
  • In Vitro Techniques
  • Male
  • Pioglitazone
  • Piperidines / blood
  • Piperidines / metabolism
  • Substrate Specificity
  • Thiazolidinediones / administration & dosage
  • Thiazolidinediones / blood
  • Thiazolidinediones / pharmacokinetics*


  • Blood Glucose
  • Capsules
  • Carbamates
  • Cytochrome P-450 Enzyme Inhibitors
  • Enzyme Inhibitors
  • Hypoglycemic Agents
  • Piperidines
  • Thiazolidinediones
  • repaglinide
  • Cytochrome P-450 Enzyme System
  • Aryl Hydrocarbon Hydroxylases
  • CYP2C8 protein, human
  • Cytochrome P-450 CYP2C8
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human
  • Pioglitazone