[Show abstract][Hide abstract] ABSTRACT: Chronic oral administration of vanadyl sulfate has recently been shown to improve the state of type 2 diabetic subjects. Mild gastrointestinal symptoms and side effects, however, have been observed in some subjects. To find safer and more effective dosages, we have developed an enteric-coated capsule containing solid vanadyl sulfate (ECC/VS), which enhances the bioavailability of vanadyl sulfate to almost double that of vanadyl sulfate solution. ECC/VS was chronically administered to treat streptozotocin-induced diabetic rats (STZ-rats), an animal model of type 1 diabetes mellitus, and an equivalent blood-glucose-lowering effect was observed at half the doses of vanadyl sulfate alone. In addition, we observed almost the same total vanadium levels in the serum after chronic administration of ECC/VS as those of vanadyl sulfate alone, suggesting that plasma vanadium levels correlate with the hypoglycaemic activity of vanadyl sulfate. These results indicate that oral ECC/VS improves the diabetic state by enhancing the uptake of vanadium in STZ-rats. These findings will be useful in designing clinical trials of vanadyl sulfate for diabetic subjects.
Full-text · Article · Jun 2005 · Journal of Pharmacy and Pharmacology
[Show abstract][Hide abstract] ABSTRACT: To treat patients suffering from diabetes mellitus, we developed several types of orally active vanadyl complexes to replace painful insulin injections, and prepared them in the form of enteric-coated capsules containing vanadium compounds. Pharmacokinetic analysis demonstrated that these capsules enhance the bioavailability of pharmacologically active vanadyl species.
Full-text · Article · Feb 2004 · Mini Reviews in Medicinal Chemistry
[Show abstract][Hide abstract] ABSTRACT: To treat both insulin-dependent type 1 and non-insulin-dependent type 2 diabetic mellitus, two potent antidiabetic vanadyl pyridone complexes, bis(1-oxy-2-pyridinethiolato)oxovanadium(IV), (VO(opt)2), and bis(1-oxy-2-pyridonato)oxovanadium(IV), (VO(opd)2), were proposed on the basis of the results of diabetic model animals by using a concept of equivalent transformation, which has been proved to be effective in changing the chemical property of a compound. Their physico-chemical properties, chemical specications, in vitro insulin-mimetic activity in isolated rat adipocytes, in vivo antidiabetic activity in both type 1 and type 2 diabetic animals, and metallokinetic feature of the vanadyl species in the blood flow of alive rats by using blood circulation monitoring-electron paramagnetic resonance (BCM-EPR) were examined. Both complexes exhibited higher in vitro insulin-mimetic activity than VOSO4, and the activity of VO(opt)2 was superior to that of VO(opd)2. However, on oral administration to type 1 diabetic rats, VO(opd)2 was more effective at lower dose than VO(opt)2. The results are supported by chemical specifications and metallokinetic (kinetic of metal disposition) parameters.
Full-text · Article · Oct 2003 · Coordination Chemistry Reviews
[Show abstract][Hide abstract] ABSTRACT: In recent years, there have been improvements in the treatment of type 2 diabetes by oral administration of vanadyl sulfate (VOSO4, VS). The maintenance of vanadyl levels in the blood of subjects with type 2 diabetes was found to be important for the insulinomimetic activity of VS. However, owing to low bioavailability of VS and the development of mild gastrointestinal symptoms and side-effects in some subjects, it is necessary to design more effective and safer dosages of VS. After discovering that VS is absorbed more thoroughly at the ileum than at other gastrointestinal sites, we investigated the absorption processes following oral administration of VS by preparing enteric-coated capsules (ECC). Although Cmax values were unchanged by the dosage forms, Tmax and MRT values associated with the enteric-coating capsulation were prolonged when compared with those observed with use of gelatin capsules (GC). An important finding was that the bioavailability of VS from ECC (9.8%) was almost double that of VS from either GC (4.0%) or the solution (4.8%). Administration of VS-containing ECC to diabetic patients is proposed to improve vanadyl absorption over that achieved by the administration of either GC or the solution.
Full-text · Article · Jun 2002 · Journal of Pharmacy and Pharmacology
[Show abstract][Hide abstract] ABSTRACT: In order to understand the insulinomimetic activity of zinc(II) complexes, we studied the metallokinetic features of zinc in the blood of normal rats given the zinc complexes, bis(maltolato)zinc(II) (Zn(mal)(2)) and bis(6-methylpicolinato)zinc(II) (Zn(6mpa)(2)) by comparing each of them with an ionic form of zinc chloride (ZnCl(2)). The bioavailability of the zinc(II) complexes following oral administration was enhanced to 1.4-1.5-fold that of ZnCl(2) with respect to zinc level. Based on the results of a metallokinetic analysis and administration method in normal rats, we examined the antidiabetic ability of the zinc(II) complexes in GK rats, a model animal of type 2 diabetes mellitus. High blood glucose levels of GK rats were normalized following intraperitoneal injections and oral administration of the zinc(II) complexes, in which the Zn(6mpa)(2) complex was found to be more effective than Zn(mal)(2). The present results are noteworthy, not only due to their potential relevance for clinical application, but also for the development of new zinc(II) complexes.
Full-text · Article · Feb 2002 · Drug Metabolism and Pharmacokinetics
[Show abstract][Hide abstract] ABSTRACT: Recently, we have shown that oral administrations of vanadyl (+4 oxidation state of vanadium) complexes normalize the blood glucose level of streptozotocin-induced diabetic rats (STZ-rats). To develop clinically useful insulin-mimetic vanadyl complexes, clarification of the pharmacokinetic features of vanadyl compounds is essential. First, we investigated the absorption processes of three compounds, an ionic form of vanadyl sulfate (VS) and the complex forms of bis(picolinato)oxovanadium(IV) (VO(pic)2) and bis(6-methylpicolinato)oxovanadium(IV) (VO(6mpa)2), from the gastrointestinal tract of healthy rats. The concentration curves of paramagnetic vanadyl species in the blood of rats after oral administration of these compounds, as monitored by X-band electron spin resonance (ESR) spectroscopy, exhibited biphasic increasing patterns, indicating that these compounds were absorbed from more than two sites in the gastrointestinal tract. The bioavailability of the compounds was enhanced in the following order on both oral and intraperitoneal administration: VO(6mpa)2 > VO(pic)2 > VS. In addition, bioavailability of the VO(6mpa)2 on ileal administration was enhanced compared with that using other administration sites such as the stomach and jejunum, and resulted in an enhancement about 1.8 fold that compared with oral administration. On the basis of these results, we concluded that the bioavailability of the complex is enhanced most effectively by delivery of the VO(6mpa)2 complex to the ileum.
Full-text · Article · Sep 2001 · Journal of Pharmacy and Pharmacology
[Show abstract][Hide abstract] ABSTRACT: Among vanadium's wide variety of biological functions, insulin-mimetic effect is the most interesting and important. 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). During our investigations, vanadylmethylpicolinate complex (VO-MPA) was found to exhibit higher insulin-mimetic activity and less toxicity than other complexes. Electron spin resonance (ESR) is capable of measuring the paramagnetic species in biological samples. We have developed the in vivo blood circulation monitoring (BCM)-ESR method to analyze the signals due to stable organic radicals in real time. In the present study, we applied this method to elucidate the global disposition of paramagnetic vanadyl species. In addition, the distribution of vanadium to several organs was investigated by neutron activation analysis (NAA). ESR spectra due to the presence of vanadyl species were obtained in the circulating blood, and their pharmacokinetic parameters were estimated using compartment models. The results indicate that vanadyl species are distributed considerably to the peripheral tissues. The exposure of vanadyl species in the blood was found to be enhanced by VO-MPA treatment. Vanadium accumulated in the bone was suggested to relate with the long-term effective character of VO-MPA. Given these results, we concluded that the pharmacokinetic character of vanadyl species is closely related with the structure and antidiabetic activity of the vanadyl compounds.