Coordination chemistry may explain pharmacokinetics and clinical response of vanadyl sulfate in type 2 diabetic patients
ABSTRACT Vanadium, abbreviated V, is an early transition metal that readily forms coordination complexes with a variety of biological products such as proteins, metabolites, membranes and other structures. The formation of coordination complexes stabilizes metal ions, which in turn impacts the biodistribution of the metal. To understand the biodistribution of V, V in oxidation state iv in the form of vanadyl sulfate (25, 50, 100 mg V daily) was given orally for 6 weeks to 16 persons with type 2 diabetes. Elemental V was determined using Graphite Furnas Atomic Absorption Spectrometry against known concentrations of V in serum, blood or urine. Peak serum V levels were 15.4 ± 6.5, 81.7 ± 40 and 319 ± 268 ng ml(-1) respectively, and mean peak serum V was positively correlated with dose administered (r = 0.992, p = 0.079), although large inter-individual variability was found. Total serum V concentration distribution fit a one compartment open model with a first order rate constant for excretion with mean half times of 4.7 ± 1.6 days and 4.6 ± 2.5 days for the 50 and 100 mg V dose groups respectively. At steady state, 24 hour urinary V output was 0.18 ± 0.24 and 0.97 ± 0.84 mg in the 50 and 100 mg V groups respectively, consistent with absorption of 1 percent or less of the administered dose. Peak V in blood and serum were positively correlated (r = 0.971, p < 0.0005). The serum to blood V ratio for the patients receiving 100 mg V was 1.7 ± 0.45. Regression analysis showed that glycohemoglobin was a negative predictor of the natural log(ln) peak serum V (R(2) = 0.40, p = 0.009) and a positive predictor of the euglycemic-hyperinsulinemic clamp results at high insulin values (R(2) = 0.39, p = 0.010). Insulin sensitivity measured by euglycemic-hyperinsulinemic clamp was not significantly correlated with ln peak serum V. Globulin and glycohemoglobin levels taken together were negative predictors of fasting blood glucose (R(2) = 0.49, p = 0.013). Although V accumulation in serum was dose-dependent, no correlation between total serum V concentration and the insulin-like response was found in this first attempt to correlate anti-diabetic activity with total serum V. This study suggests that V pools other than total serum V are likely related to the insulin-like effect of this metal. These results, obtained in diabetic patients, document the need for consideration of the coordination chemistry of metabolites and proteins with vanadium in anti-diabetic vanadium complexes.
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ABSTRACT: The influence of metals in biology has become more and more apparent within the past century. Metal ions perform essential roles as critical scaffolds for structure and as catalysts in reactions. Speciation is a key concept that assists researchers in investigating processes that involve metal ions. However, translation of the essential area across scientific fields has been plagued by language discrepancies. To rectify this, the IUPAC Commission provided a framework in which speciation is defined as the distribution of species. Despite these attempts, contributions from inorganic chemists to the area of speciation have not fully materialized in part because the past decade's contributions focused on technological advances, which are not yet to the stage of measuring speciation distribution in biological solutions. In the following, we describe how speciation influences the area of metals in medicine and how speciation distribution has been characterized so far. We provide two case studies as an illustration, namely, vanadium and iron. Vanadium both has therapeutic importance and is known as a cofactor for metalloenzymes. In addition to being a cation, vanadium(V) has analogy with phosphorus and as such is a potent inhibitor for phosphorylases. Because speciation can change the metal's existence in cationic or anionic forms, speciation has profound effects on biological systems. We also highlight how speciation impacts iron metabolism, focusing on the rather low abundance of biologically relevant iron cation that actually exists in biological fluids. fluids. Furthermore, we point to recent investigations into the mechanism of Fenton chemistry, and that the emerging results show pH dependence. The studies suggest formation of Fe(IV)-intermediates and that the generally accepted mechanism may only apply at low pH. With broader recognition toward biological speciation, we are confident that future investigations on metal-based systems will progress faster and with significant results. Studying metal complexes to explore the properties of a potential "active species" and further uncovering the details associated with their specific composition and geometry are likely to be important to the action.Inorganic Chemistry 09/2013; 52(21). DOI:10.1021/ic4007873 · 4.79 Impact Factor
- Inorganic Chemistry 11/2013; 52(21):12181-3. DOI:10.1021/ic402341n · 4.79 Impact Factor
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ABSTRACT: The interaction of V(IV)O(2+) ion with hemoglobin (Hb) was studied with the combined application of spectroscopic (EPR), spectrophotometric (UV-vis), and computational (DFT methods) techniques. Binding of Hb to V(IV)O(2+) in vitro was proved, and three unspecific sites (named α, β, and γ) were characterized, with the probable coordination of His-N, Asp-O(-), and Glu-O(-) donors. The value of log β for (VO)Hb is 10.4, significantly lower than for human serum apo-transferrin (hTf). In the systems with V(IV)O potential antidiabetic compounds, mixed species cis-VOL2(Hb) (L = maltolate (ma), 1,2-dimethyl-3-hydroxy-4(1H)-pyridinonate (dhp)) are observed with equatorial binding of an accessible His residue, whereas no ternary complexes are observed with acetylacetonate (acac). The experiments of uptake of [VO(ma)2], [VO(dhp)2], and [VO(acac)2] by red blood cells indicate that the neutral compounds penetrate the erythrocyte membrane through passive diffusion, and percent amounts higher than 50% are found in the intracellular medium. The biotransformation of [VO(ma)2], [VO(dhp)2], and [VO(acac)2] inside the red blood cells was proved. [VO(dhp)2] transforms quantitatively in cis-VO(dhp)2(Hb), [VO(ma)2] in cis-VO(ma)2(Hb), and cis-VO(ma)2(Cys-S(-)), with the equatorial coordination of a thiolate-S(-) of GSH or of a membrane protein, and [VO(acac)2] in the binary species (VO)xHb and two V(IV)O complexes with formulation VO(L(1),L(2)) and VO(L(3),L(4)), where L(1), L(2), L(3), and L(4) are red blood cell bioligands. The results indicate that, in the studies on the transport of a potential pharmacologically active V species, the interaction with red blood cells and Hb cannot be neglected, that a distribution between the erythrocytes and plasma is achieved, and that these processes can significantly influence the effectiveness of a V drug.Inorganic Chemistry 01/2014; 53(3). DOI:10.1021/ic402366x · 4.79 Impact Factor