Influence of Efavirenz and Nevirapine on the Pharmacodynamics and Pharmacokinetics of Gliclazide in Rabbits

Abstract

Background : Since polypharmacy is very common practice in diabetic patients, the study of drug-drug interactions is an imperative rational approach with respect to safety and efficacy determination. Gliclazide is a widely used drug for the treatment of type 2 diabetes. Efavirenz and nevirapine are widely used non-nucleoside reverse transcriptase inhibitors (NNRTIs) with fewer side effects concerning diabetic complications.The objective of the study is to investigate the effect of selected NNRTIs on the pharmacodynamics and pharmacokinetics of gliclazide in rabbits with respect to safety and efficacy of the combination. Methods : Influence of selected NNRTIs on the activity of gliclazide was determined by conducting a single dose interaction followed by multiple dose interaction study with two groups consisting of 6 normal rabbits each. Each group was treated with an oral dose of 5.6 mg/1.5 kg bd. wt. of gliclazide, interacting drug treatment (42 mg/1.5 kg bd. wt. of efavirenz or 14 mg/1.5 kg bd. wt. of nevirapine) and their combination with a one week washout period between each treatment. One week washout after this single dose interaction study, each group was continued with the daily treatment of interacting drug for the next eight days and then the combined treatment on the ninth day. Blood samples were collected at regular intervals by marginal ear vein puncture in rabbits and were analyzed for blood glucose by GOD/POD method and insulin by radioimmunoassay method. The serum gliclazide levels were estimated by HPLC method and pharmacokinetic analysis was conducted by noncompartmental analysis using WinNonlin software. Results : In combination, efavirenz significantly (P less than 0.05) reduced the pharmacodynamic activity and serum levels of gliclazide. The pharmacokinetic parameters of gliclazide were significantly (P less than 0.05) altered. The percent decrease of serum gliclazide concentration level is 24.23% and 15.20% following single dose and multiple dose administration of efavirenz, respectively. In combination, nevirapine has no significant effect on the pharmacodynamics and pharmacokinetics of gliclazide in rabbits. Conclusions : The significant pharmacokinetic interaction of efavirenz at metabolic level by CYP3A4 induction results in decreased serum gliclazide levels and pharmacodynamic activity of gliclazide. The combination of nevirapine and gliclazide was proved to be safe. doi:10.4021/jem34w