Evaluation of efficacy and safety of artesunate and its active metabolite, dihydroartemisinin, in streptozotocin-induced diabetes rats by blood pharmacokinetic analysis

Background: Artesunate (AS), an anti-malarial drug, is hydrolyzed by serum esterase for its conversion to the active metabolite, dihydroartemisinin (DHA). Evidence for the clinical effectiveness of AS is growing; however, little information is available on special populations such as patients with diabetes mellitus (DM). In addition, although erythrocytes are considered as a target site, the blood pharmacokinetics of AS and DHA remain unclear. Therefore, the blood pharmacokinetics of AS and DHA were investigated in DM rats in the present study. Methods: DM rats were prepared by intraperitoneal injection of streptozotocin. An in vitro protein binding study of AS and DHA was performed by the ultrafiltration method. Plasma and blood samples were collected after the intravenous administration of AS, to analyze pharmacokinetics of AS and DHA. Blood to plasma ratios (BP ratio), as an index of erythrocyte distribution, were then calculated by dividing blood concentrations by plasma concentrations. Results: The protein bindings of AS and DHA were 83.7% and 92.6% in control rats and 86.2% and 92.2% in DM rats, respectively. All concentration profiles in this study were best fit by a two compartment model; the plasma and blood pharmacokinetic parameters of AS and DHA in DM rats were not significantly different from those in control rats. The BP ratio of AS was at an extremely low level (approximately 0.5) just after its administration, whereas that of DHA was maintained above 1.0 throughout the study; however, no significant changes were observed between control and DM rats. Conclusion: The glycation of albumin with DM did not affect the protein bindings of AS or DHA. No significant changes were observed in the conversion of AS to DHA by serum esterase or disposition of DHA in DM rats. The blood concentrations of DHA declined in parallel with plasma concentrations and the distribution of DHA to erythrocytes was good. In conclusion, the efficacy and safety of both AS and DHA were tolerated in DM rats with DHA having more favorable characteristics than AS.