Nevirapine in an animal model of pre-diabetes: study of drug pharmacokinetic and its effects on fasting glycemia and insulin resistance

Dissertação para obtenção do Grau de Mestre em Biotecnologia

The increased incidence of type II diabetes has emerged as a major concern in controlled human immunodeficiency virus (HIV)infection. There is a general lack of data to support the best combined antiretroviral therapy (cART) option to treat HIV-patients with pre-diabetes and nevirapine has been described has a glucose-friendly antiretroviral. On the other hand, it is known that diabetes could influence the pharmacokinetics of several drugs. This aspect is particularly relevant for drugs with narrow therapeutic window, which is the case of nevirapine. To understand if nevirapine is a good choice for pre-diabetic HIV-patients, the effect of insulin resistance in NVP pharmacokinetics as well as the effect of nevirapine on insulin resistance, fasting glycemia and mean arterial pressure was evaluated. Moreover, nevirapine effect on thiols content, an endogenous antioxidant defence system, was also evaluated. To achieve the main goal four groups of female Wistar rat were used: a control group, a control group treated with nevirapine, an insulin resistant group and an insulin resistant group treated with nevirapine. An influence of a pre-diabetic status on nevirapine pharmacokinetic was found. Nevirapine and its phase I metabolites presented changes in disposition and the metabolite profile pattern was changed. Moreover, nevirapine, in a pre-diabetic perspective, is associated with a beneficial effect on fasting glycemia, while it has no effect on sensitivity to insulin or in arterial pressure. Furthermore, nevirapine is associated with a lower degradation of total glutathione. Nevirapine might be a good option for HIV-infected patients at higher risk of develop diabetes or in pre-diabetic condition. Moreover, while further studies are necessary to consolidate this issue, nevirapine might be less toxic in pre-diabetes. Although, the decreased bioavailability of nevirapine in pre-diabetes requires special attention, as an adjustment of nevirapine dose might be required in this subpopulation.

Portuguese Foundation for Science and Technology - PTDC/QUI-QUI/113910/2009, PTDC/SAU-ORG/111417/2009