Abstract
<p>The metabolic syndrome in HIV infected patients is particularly associated with the use protease inhibitors. Atazanavir is an inhibitor of the cytochrome P 450 (CYP) system, in particular CYP3A4 and CYP2C9 which can affect the metabolism of several drugs. To treat metabolic syndrome in HIV patients repaglinide is used and it is a short acting insulin secretagogues undergoing metabolism with CYP 3A4 and CYP 2C8 enzyme system. The purpose of this study was to assess the possible pharmacokinetic and pharmacodynamic drug interaction of repaglinide and atazanavir in healthy, diabetic and impaired hepatic function rats. Human oral therapeutic doses of atazanavir and repaglinide were extrapolated to rats based on the body surface area. The pharmacokinetic parameters and blood glucose concentrations of repaglinide were determined after oral administration of repaglinide alone (0.5 mg/kg) and in the presence of atazanavir (36 mg/kg) in normal, diabetic and hepatic impaired rats. The pharmacokinetics (PK) and blood glucose concentrations of repaglinide were significantly altered in the presence of atazanavir. The peak plasma concentration (C<sub>max</sub>), area under the plasma concentration time profile (AUC) and elimination half-life of repaglinide were significantly (P&lt;0.0001) increased. The repaglinide clearance (CL) was significantly (P&lt;0.0001) decreased in the presence of atazanavir treatment. In the presence of atazanavir, repaglinide hypoglycaemic activity was increased significantly (P&lt;0.0001) when compared with the repaglinide control group. The present study demonstrated the significant difference in the PK/PD changes due to the enhanced bioavailability and decreased total body clearance of repaglinide may be due to the inhibition of the CYP P450 metabolic system, OATP and P-gp transporters by atazanavir.</p>
Highlights
The prevalence and incidence of metabolic syndrome, diabetes mellitus, was increasing in HIV patients
No interfering peaks were observed in blank plasma chromatograms at atazanavir and repaglinide retention time indicating the selectivity of the present method
The inter-day precision was determined from analysis of standard samples on three consecutive days and the relative standard deviation was found to be
Summary
The prevalence and incidence of metabolic syndrome, diabetes mellitus, was increasing in HIV patients. ADMET & DMPK 4(3) (2016) 269-279 antiretroviral therapy (HAART) has contributed considerable reductions in HIV viral load and increased in CD4 lymphocyte numbers, thereby slowing disease progression and improving patient survival. Despite this clinical success, it is recognized that PI-based therapy is correlated with a number of significant metabolic complications, including lipodystrophy, hyperlipidaemia, and insulin resistance. Patient-specific factors that affect enzymatic activity, protein binding, or liver blood flow would potentially result in significant alterations in drug disposition and therapeutic response. An understanding of the pharmacokinetic basis of hepatic drug elimination is helpful to conceptualize and quantify altered drug disposition in patients with liver dysfunction [2]
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