Effect of protease inhibitors (indinavir and ritonavir) on the pharmacokinetics of gliclazide in rabbits

Kilari Eswar Kumar¹, Shaik Mastan^2,3
1Pharmacology Division, University College of Pharmaceutical Sciences, Andhra University, Visakhapatnam, Andhra Pradesh, India; ²Research and Development Cell, Jawaharlal Nehru Technological University, Hyderabad, Andhra Pradesh, India; ³Cytel Statistical Software and Services Pvt Ltd, Pune, Maharashtra, India

Abstract: The objective of this study was to investigate the effect of protease inhibitors (indinavir and ritonavir) on the pharmacokinetics of gliclazide in rabbits and to evaluate the mechanism of interaction of the combination. Studies in rabbits were conducted with oral doses of gliclazide, selected protease inhibitor, and their combination with a 1-week washout period between each treatment (single dose followed by multiple dose treatment). Blood samples were collected at regular time intervals by marginal ear vein puncture and serum gliclazide levels were analyzed by high-pressure liquid chromatography. Pharmacokinetic analysis was performed by noncompartmental analysis using WinNonlin Software. In combination, ritonavir significantly increased serum gliclazide levels and altered the pharmacokinetic parameters of gliclazide in rabbits while indinavir had no significant effect. The percentage increase of serum gliclazide level was 22.34% and 27.78% following single-dose and multiple-dose treatment of ritonavir, respectively. The interaction of ritonavir with gliclazide is pharmacokinetic at a metabolic level (by CYP3A4 inhibition) in normal rabbits, while the interaction of indinavir with gliclazide is pharmacodynamic, which needs dose adjustment, and care should be taken when these combinations are prescribed for their clinical benefit in diabetic patients.

Keywords: gliclazide, indinavir, ritonavir, diabetes, HIV infection, pharmacokinetics