Pharmacokinetic interaction between efavirenz and ketoconazole in rats

Xenobiotica. 2009 Feb;39(2):135-9. doi: 10.1080/00498250802621698.


1. It is well known that efavirenz and ketoconazole act as an inducer and inhibitor of CYP3A4, respectively. As a result of these actions, co-administration of these drugs may result in changes in the pharmacokinetic parameters of one or both of them. 2. Duodenum-cannulated rats have been used to compare the effect of intraduodenal (KC(i.d.)) and intravenous administration of ketoconazole (KC(i.v.)) on the pharmacokinetics of efavirenz after intraduodenal administration, as well as the potential effect of efavirenz as a CYP450 inducer on ketoconazole pharmacokinetic profile. 3. While KC(i.v.) did not show any significant effect on efavirenz pharmacokinetic profile, KC(i.d.) increased significantly (p < 0.05) the peak concentration (C(max)) and the area under the plasma concentration-time curve (AUC) of efavirenz by 25.5% and 44.5%, respectively. In addition, the time necessary to reach peak concentration (T(max)) increased markedly by 71%. However, the mean total clearance (CL/F) of efavirenz was significantly decreased by 45%. Efavirenz did not produce any alteration in ketoconazole pharmacokinetics. 4. These findings suggest that when the treatment starts with enteral administration of ketoconazole, the inhibitor effect on CYP450 prevails over the inducer effect of efavirenz.

MeSH terms

  • Alkynes
  • Animals
  • Anti-HIV Agents / administration & dosage
  • Anti-HIV Agents / pharmacokinetics*
  • Anti-HIV Agents / pharmacology
  • Antifungal Agents / administration & dosage
  • Antifungal Agents / pharmacokinetics*
  • Antifungal Agents / pharmacology
  • Benzoxazines / administration & dosage
  • Benzoxazines / pharmacokinetics*
  • Benzoxazines / pharmacology
  • Cyclopropanes
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System / metabolism
  • Drug Administration Schedule
  • Drug Interactions
  • Ketoconazole / administration & dosage
  • Ketoconazole / pharmacokinetics*
  • Ketoconazole / pharmacology
  • Male
  • Rats
  • Rats, Wistar


  • Alkynes
  • Anti-HIV Agents
  • Antifungal Agents
  • Benzoxazines
  • Cyclopropanes
  • Cytochrome P-450 Enzyme Inhibitors
  • Cytochrome P-450 Enzyme System
  • Cyp3a2 protein, rat
  • Cytochrome P-450 CYP3A
  • efavirenz
  • Ketoconazole