Pharmacokinetic analysis of insulin-mimetics vanadium complexes in rats -metallokineticanalysis by BCM-ESR method-

Abstract

Biological functions of vanadium have been investigated by many researchers. Especially, the insulin-like effect of vanadium is the most remarkable. Recently, vanadyl ion (+4 oxidation state of vanadium) and its complexes have been shown to normalize the blood glucose levels of streptozotocin-induced diabetic rats (STZ-rats). We have examined to find more effective vanadyl complexes with insulin-mimetic activity and prepared less toxic complexes with several types of coordination mode. Among them, vanadyl-methylpicolinate complex (VO-MPA) was found to exhibit higher insulin- mimetic activities and less toxic than other complexes as evaluated by both in vitro and in vivo experiments. Electron spin resonance (ESR) is available to measure the paramagnetic compounds in biological samples. We have developed the in vivo blood circulation monitoring-electron spin resonance (BCM-ESR) method to analyze the ESR signals due to paramagnetic metal ions and stable radicals in real time. In the present pharmacokinetic investigation to elucidate the relationship between the blood glucose normalizing effect and global disposition of vanadium, we report first the experiments, in which the BCM-ESR method was applied to evaluate the disposition of vanadyl states in circulating blood after intravenous administration to male Wistar rats. ESR spectra due to vanadyl state were obtained in circulating blood, and pharmacokinetic parameters for them were estimated by using the compartment model. The results of the experiments indicated that vanadium considerably distributed to peripheral tissues and eliminated from the body through urine, and the accumulation of vanadium in the tissue was enhanced by VO-MPA treatment. The long-acting property of VO-MPA was suggested by the incorporation and accumulation of vanadium in the bone. We conclude that the tissue distribution of vanadium is closely related with the antidiabetic activity of the vanadyl complex.