Disposition and Plasma Protein Binding of Halofantrine in Experimental Diabetic Rats

Daniyan, Michael Oluwatoyin (2015-04-20)


This study investigated the effects of diabetes on the disposition of halofantrine and elucidated the contribution of plasma protein binding to any observed changes in the drug pharmacokinetics, with a view to propose the implication of such influences on the use of halofantrine in the treatment of malaria in diabetics. Pharmacokinetics study was performed using 96 white Albino rats, randomly divided into two groups (Control and Diabetic) with 48 rats per group. Each group was further subdivided into 12 subgroups of 4 rats each, representing time points for blood sample collection. Diabetes was induced by a single intraperitoneal administration of 150 mg/kg alloxan monohydrate and allowed a 5% w/v glucose drink for 24 hours. Following a single dose oral administration of 8 mg/kg body weight halofantrine hydrochloride suspension, blood samples were collected at predetermined time intervals and analyzed for halofantrine (Ht) and its major metabolite, desbutylhalofantrine (DHf), using a validated HPLC method. Also plasma bilirubin, cholesterol, triglycerides and total protein were determined using established methods and commercially available reagent kits. Plasma protein binding studies of halofantrine and desbutylhalofantrine in control and diabetic groups were determined using the Erythrocyte/Plasma partitioning method. Data was analyzed using Student's t-test and One way analysis of variance (ANOVA) followed by post hoc Student-Newman-Keel test. Pair wise relationship was determined using Pearson correlation coefficient. Results showed that the mean peak plasma concentrations (Cmax) of halofantrine and desbutylhalofantrine in control (0.9301 ± 0.0770 μg/ml and 0.4003 ± 0.0316 μg/ml) were significantly higher than those obtained in diabetic rats (0.3643 ± 0.0149 μg/ml and 0.2063± 0.0398 μg/ml) respectively (p < 0.05). The Tmax, AUC0–∞, and CL/F were comparable between the two groups of rats but the V(d)β/F increased by up to 26% in diabetic compared to normal rats. The increase in V(d)β/F was associated with an increase in elimination half life by 19%. The ratio of AUC (AUCDHf / AUCHf(0.72)) were comparable between the two groups of rats indicating that diabetes did not alter the metabolism of halofantrine. The binding of halofantrine in diabetic plasma (0.0199 ± 0.0043) was significantly higher when compared to control (0.1039 ± 0.0068) at p < 0.05. This increased binding correlated well with increased level of plasma triglycerides concentrations (r > 0.60), indicating that lipids constitute the major binding site for the drug and its metabolite. The results indicated that elevated levels of triglycerides-associated lipoproteins in diabetic condition might have resulted in increased transportation of Hf and DHf bound lipoproteins across the cell membranes resulting in the observed increase in V(d)β/F of the drug and a consequent decrease in their mean plasma concentrations. In conclusion the study showed that diabetes induced an alteration in the pharmacokinetics of halofantrine, especially in its Cmax, which could be attributed to differential binding to plasma constituents between diabetic and normal rats.