Effect of antiretroviral drugs on the pharmacodynamics of gliclazide with respect to glucose–insulin homeostasis in animal models

Abstract

The objective of this study was to investigate the effect of oral administration of antiretroviral drugs (indinavir, ritonavir, atazanavir, efavirenz and nevirapine) on the pharmacodynamics of gliclazide in rats (normal and diabetic) and rabbits with respect to glucose–insulin homeostasis to evaluate the safety and effectiveness of the combinations. Blood samples were collected at regular time intervals in rats from retro orbital puncture and by marginal ear vein puncture in rabbits. All the blood samples were analyzed for blood glucose by glucose oxidase–peroxidase method and insulin by a radio immuno assay method. The insulin resistance index and β-cell function were determined by a homeostasis model assessment. Indinavir and ritonavir alone had significant impact on glucose–insulin homeostasis in animal models among the antiretroviral drugs used in our study. In combination, indinavir and efavirenz significantly reduced the activity of gliclazide, while ritonavir and atazanavir significantly increased the activity of gliclazide. However, nevirapine had no significant effect on the activity of gliclazide. From this study we conclude that glucose–insulin homeostasis disorders associated with antiretroviral drugs are not class-specific, but are drug-specific. So care should be taken when indinavir, ritonavir, atazanavir and efavirenz are prescribed for diabetic patients.

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

“…This consistency addresses the probable correlation of preclinical animal studies with studies on human subjects, and their use might provide important insights into the mechanisms of drug interactions which would improve their understanding and provide the basis for rational therapy. Thus our results indicating gliclazide peak concentration at 3 hours and absence of biliary excretion and enterohepatic cycling in rabbits are consistent with our former pharmacodynamic studies [8][9][10] as well as the literature. Indinavir is reported to be metabolized by CYP3A4 and an inhibitor of the cytochrome P450 isoform CYP3A4.…”

“…8,9 Gliclazide (5.6 mg/1.5 kg body weight) solution was prepared by dissolving it in a few drops of 0.1N NaOH then made up to the volume with distilled water. 10 Two groups of 6 rabbits each were administered with 5.6 mg/1.5 kg body weight of gliclazide orally. The same group was administered with interacting drug (indinavir or ritonavir) and the combination of PI and gliclazide.…”

“…Gliclazide is rapidly absorbed in all species (man, monkey, beagle, rabbit, and rat) with similar excretion in all species and inter-species variation in half-life. 5,27 Our results in rabbits showed that gliclazide produced peak concentration at 3 hours with no second peak, while in rat models 5,[8][9][10]20,21 and humans 28 a second peak is reported to be common due to the presence biliary excretion and enterohepatic cycling of gliclazide. According to Davis et al 29 the extent of mean enterohepatic recirculation observed in humans was consistent with animal data.…”

“…[8][9][10] These studies showed that both indinavir and ritonavir alone have a tendency to produce hyperglycemia and alterations in insulin-glucose homeostasis, and a ccelerated the diabetic condition in animal models. In combination, indinavir significantly reduced the effect of gliclazide while ritonavir increased the effect of gliclazide (contrary to its individual potency to exacerbate diabetes) and confirmed the existence of significant interactions.…”

Influence of curcumin on the pharmacodynamics and pharmacokinetics of gliclazide in animal models

“…Oral dose formulation for curcumin was prepared by suspending in 0.5% carboxymethyl cellulose Na. Gliclazide solution was prepared by dissolving in few drops of 0.1 N NaOH and the final volume was made with water 17. The design of the study is as follows:

Stage 1: Pharmacodynamic interaction in normal rats 3

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