Pharmacokinetic interaction between itraconazole and metformin in rats: competitive inhibition of metabolism of each drug by each other via hepatic and intestinal CYP3A1/2

Br J Pharmacol. 2010 Oct;161(4):815-29. doi: 10.1111/j.1476-5381.2010.00913.x.


Background and purpose: Fungal infection is prevalent in patients with diabetes mellitus. Thus, we investigated whether a pharmacokinetic interaction occurs between the anti-fungal agent itraconazole and the anti-glycaemic drug metformin, as both drugs are commonly administered together to diabetic patients and are metabolized via hepatic CYP3A subfamily in rats.

Experimental approach: Itraconazole (20 mg·kg(-1)) and metformin (100 mg·kg(-1)) were simultaneously administered i.v. and p.o. to rats. Concentrations (I) of each drug in the liver and intestine, maximum velocity (V(max)), Michaelis-Menten constant (K(m)) and intrinsic clearance (CL(int) ) for the disappearance of each drug, apparent inhibition constant (K(i) ) and [I]/K(i) ratios of each drug in the liver and intestine were determined. Also the metabolism of each drug in rat and human CYPs was measured in vitro.

Key results: After simultaneous administration of both drugs, either i.v. or p.o., the total area under the plasma concentration-time curve from time zero to infinity (AUC)s of itraconazole and metformin were significantly greater than that of either drug administered alone. The metabolism of itraconazole and metformin was significantly inhibited by each other via CYP3A1 and 3A2 in rat and 3A4 in human microsomes.

Conclusions and implications: The significantly greater AUCs of itraconazole and metformin after i.v. administration of both drugs are probably due to competitive inhibition of the metabolism of each drug by each other via hepatic CYP3A1/2. Whereas after oral administration of both drugs, the significantly greater AUCs of each drug administered together than that of either drug alone is mainly due to competitive inhibition of intestinal metabolism of each drug by each other via intestinal CYP3A1/2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antifungal Agents / administration & dosage
  • Antifungal Agents / pharmacokinetics
  • Area Under Curve
  • Aryl Hydrocarbon Hydroxylases / metabolism*
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Interactions
  • Humans
  • Hypoglycemic Agents / administration & dosage
  • Hypoglycemic Agents / pharmacokinetics
  • Intestinal Mucosa / metabolism
  • Intestines / enzymology
  • Itraconazole / administration & dosage
  • Itraconazole / pharmacokinetics*
  • Liver / enzymology
  • Liver / metabolism
  • Male
  • Membrane Proteins / metabolism*
  • Metformin / administration & dosage
  • Metformin / pharmacokinetics*
  • Microsomes, Liver / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Tissue Distribution


  • Antifungal Agents
  • Hypoglycemic Agents
  • Membrane Proteins
  • Itraconazole
  • Cytochrome P-450 Enzyme System
  • Metformin
  • Aryl Hydrocarbon Hydroxylases
  • Cyp3a2 protein, rat
  • Cyp3a23-3a1 protein, rat
  • Cytochrome P-450 CYP3A