Abstract

It was hypothesized in this study that alterations in plasma lipoprotein profile and disturbed gastrointestinal motility as observed in diabetes mellitus may influence the disposition of halofantrine (HF), a highly lipophilic antimalarial drug. Therefore, using a rat model of diabetes mellitus induced by administration of alloxan monohydrate, the effects of the disease on the pharmacokinetics of HF was investigated. Also, the drug binding to normal and diabetic plasma components was determined. Results showed that the mean C_max values of HF and its major metabolite, desbutylhalofantrine (DHF), were markedly higher (up to 2.5 times) in the control than in diabetic rats (p < 0.05). Also, the early AUC (AUC_{0 – 12}) and rate of drug absorption (C_max /AUC_0-∞) were markedly reduced by 40 and 58%, respectively, in diabetic compared to control group. However, the T_max, AUC_0-∞, and elimination T_1/2 of HF were comparable between the two groups (p > 0.05). The binding of HF and DHF in diabetic plasma was significantly higher when compared to control (p < 0.05) and correlated well with increased triglycerides concentrations. Elevated plasma drug levels expected in diabetes due to observed marked increase in drug binding to plasma components appear to be counterbalanced by other pharmacokinetic-modulating processes induced by the disease. It is suggested that the significantly reduced C_max of the drug and its metabolite in diabetes may have clinical implications since the clinical efficacy of HF is influenced by its peak plasma concentrations.

Key words: Halofantrine, pharmacokinetics, drug plasma binding, lipoproteins, diabetes mellitus.