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Timestamp: 2019-04-21 18:11:59+00:00

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The reactions of oral V(V/IV) anti-diabetic drugs within the gastrointestinal environment (particularly in the presence of food) are a crucial factor that affects their biological activities, but to date these have been poorly understood. In order to build up reactivity–activity relationships, the first detailed study of the reactivities of typical V-based anti-diabetics, Na3VVO4 (A), [VIVO(OH2)5](SO4) (B), [VIVO(ma)2] (C, ma = maltolato(−)) and (NH4)[VV(O)2(dipic)] (D, dipic = pyridine-2,5-dicarboxylato(2−)) with simulated gastrointestinal (GI) media in the presence or absence of food components has been performed by the use of XANES (X-ray absorption near edge structure) spectroscopy. Changes in speciation under conditions that simulate interactions in the GI tract have been discerned using correlations of XANES parameters that were based on a library of model V(V), V(IV), and V(III) complexes for preliminary assessment of the oxidation states and coordination numbers. More detailed speciation analyses were performed using multiple linear regression fits of XANES from the model complexes to XANES obtained from the reaction products from interactions with the GI media. Compounds B and D were relatively stable in the gastric environment (pH ∼ 2) in the absence of food, while C was mostly dissociated, and A was converted to [V10O28]6−. Sequential gastric and intestinal digestion in the absence of food converted A, B and D to poorly absorbed tetrahedral vanadates, while C formed five- or six-coordinate V(V) species where the maltolato ligands were likely to be partially retained. XANES obtained from gastric digestion of A–D in the presence of typical food components converged to that of a mixture of V(IV)–aqua, V(IV)–amino acid and V(III)–aqua complexes. Subsequent intestinal digestion led predominantly to V(IV) complexes that were assigned as citrato or complexes with 2-hydroxyacidato donor groups from other organic compounds, including certain carbohydrates. The absence of strong reductants (such as ascorbate) in the food increased the V(V) component in gastrointestinal digestion products. These results can be used to predict the oral bioavailability of various types of V(V/IV) anti-diabetics, and the effects of taking such drugs with food.
Significant issues were apparent when V(V) and V(IV) complexes were used as anti-diabetics in animal experiments and human phase I clinical trials including the following: (i) a distinct dichotomy of response (either achieved early in the treatment or not achieved at all);1 and (ii) a poor correlation between the glucose-lowering effect and V levels in the blood.12 In addition, administration together with food greatly reduced the oral bioavailability of such complexes, which suggested ligand substitution with food components.1,13 Animal studies using the 14C-labelled V(IV) ethylmaltolato complex showed that the compound dissociated within an hour after the ingestion (in fed animals), most likely in the stomach.1,12a These data indicated that the interactions with gastrointestinal media (including food components) were crucial for controlling the biological activities of V-based oral anti-diabetics.1,4,14,15 However, apart from some stability studies in acidic or neutral aqueous solutions (resembling gastric or intestinal environments, respectively),11,16 no reactivity studies of anti-diabetic V(V) or V(IV) complexes in gastrointestinal media have been performed, as yet.
The model V(V) and V(IV) complexes (Chart 1) were either purchased from Aldrich (A and B, purity >99%), or synthesized by modified literature procedures (C, D, F, G, I and J)23–29 and characterized by elemental analyses, infrared spectroscopy and electrospray mass spectrometry, as described previously.22 Note that V-oxido binding in V(IV) and V(V) complexes (except for A, Chart 1) is represented with triple, rather than double, bonds (contrary to the common convention). The triple bond arises from a combination of one σ and two π bonds.30,31 Published XANES spectra for E (the mineral pascoite, Ca3[VV10O28]·17H2O)32 and H (0.10 M solution of VIIICl3 in 1.0 M HCl)33 were also used in the fits. Other reagents of analytical or higher purity grade were purchased from Sigma-Aldrich or Merck, and used without further purification. Water was purified by the Milli-Q technique. The pH values of the reaction solutions were measured by a HI 9023 pH-meter (Hanna Instruments) equipped with a PHR-146 solid-state micro-pH electrode (Lazar Research Laboratories), and the instrument was calibrated daily with pH standard solutions (Sigma).
a Designations of the initial compounds (A–D) correspond to those in Chart 1, and the numbers (1–6) designate the treatment conditions. The XANES spectra for A5 and C5 were collected at the ANBF, and all the other spectra were collected at the AS (see Experimental for details). b In all the experiments, the total V concentrations in the reaction mixtures were 1.0 mM. Details of the treatment conditions are described in the Experimental section. c A XANES spectrum or a combination of spectra of model V(V), V(IV) and V(III) complexes (Chart 1) that provide the best possible match for the XANES spectrum of the corresponding sample (see Fig. 3 and Fig. S1 and S2, ESI). Standard deviations were calculated using Origin software46 as a part of multiple linear regression procedure. d Regression coefficient for the superposition of the sample and model spectra (see Fig. S2, ESI for multiple linear regression results). e Since nearly identical XANES spectra were obtained from samples A3, B3, C3 and D3 (Fig. S1d and e, ESI), the averaged spectrum was used for the modelling. f Artificial meal 1 was a commercial semi-synthetic meal ("liquid breakfast");39 and artificial meal 2 was prepared from separate components;14,15 see ESI for the composition of the both meals.
Modified literature procedures14,15,37,38 were used for artificial digestion of A–D in the presence of typical food components and digestive enzymes. For experiments A3–D3 and A4–D4 (Table 1), an aliquot (10 mL) of commercial liquid semi-synthetic meal ("liquid breakfast", Sanitarium, Australia; detailed composition is given in ESI†)39 was acidified to pH = 1.8 (from the initial value of 6.7) by dropwise addition of concentrated HCl (∼0.10 mL of 10 M solution), then pepsin solution (0.014 g porcine pepsin in 0.60 mL of 0.10 M HCl) was added. Aliquots (1.0 mL) of the resultant solution were immediately mixed with A–D to [V]final = 1.0 mM, and incubated for 1 h at 310 K in a rocking water bath with free access to air (simulated gastric digestion), followed either by freeze-drying of the samples (experiments A3–D3), or by simulated intestinal digestion (experiments A4–D4). For the latter experiments, NaHCO3 solution (1.0 M, ∼0.15 mL) and pancreatin-bile solution (0.010 g of porcine pancreatin and 0.050 g of porcine bile extract in 0.25 mL of 0.10 M NaHCO3) were added dropwise to the samples (to final pH = 7.5), followed by incubation for a further 2 h at 310 K, and freeze-drying of the resultant mixtures. Experiments A5 and C5 (Table 1) were performed in the same manner as A4–D4, except that the semi-synthetic meal was freshly prepared from separate components and did not contain vitamin additions (see ESI† for details). For experiment C6 (Table 1), compound C (in a mixture with BN, see above) was dissolved in HEPES-buffered saline (20 mM HEPES, 140 mM NaCl, pH = 7.40; where HEPES = 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)40 under a stream of Ar (to avoid V(IV) oxidation to V(V))23 to [V]final = 1.0 mM, BN was removed by centrifugation, and the resultant solution was immediately frozen at ∼195 K and freeze-dried.
A comparison of XANES spectra (5460–5520 eV) of the parent complexes (A–D in Chart 1) with those of the reaction products in artificial gastrointestinal media (A1–D1, A2–D2, A3–D3 and A4–D4 in Table 1) is shown in Fig. 1. Key XANES parameters (position and intensity of the pre-edge absorbance, edge energy at the half-edge jump, and post-edge absorbance intensity) for these samples are plotted in Fig. 2, where they are compared with the corresponding parameters for model V(V/IV/III) complexes (designated with red ellipses in Fig. 2).22 Comparison of XANES of the reaction products (Table 1) with those of selected model complexes (Chart 1), or their linear combinations, are shown in Fig. 3 and Fig. S1 and S2 (ESI†), and the best fits to the XANES from each sample are summarized in Table 1.
Fig. 1 Comparison of XANES of initial complexes (A–D) with those of the reaction products with artificial digestion systems. Designations of the samples correspond to those in Chart 1 and Table 1. All the data were collected at ∼295 K in fluorescence detection mode for solid samples (mixtures of model complexes with BN or freeze-dried reaction mixtures; see Experimental for details).
Fig. 3 Comparison of selected XANES spectra of the reaction products of A–D with those of model V(V), V(IV) and V(III) complexes (see also Fig. S1 and S2 in ESI;† designations correspond to those in Chart 1 and Table 1). All the data were collected at ∼295 K in fluorescence detection mode for solid samples (freeze-dried reaction mixtures or mixtures of model complexes with BN; see Experimental section for details).
In summary, XANES data pointed to the relative stabilities of B and D in the acidic environment of the stomach (in the absence of food) compared with A and C, which converted predominantly to [V10VO28]6− and [VIVO(OH2)5]2+, respectively, under these conditions. These findings were consistent with the literature data on the reactivity of A–D in acidic aqueous solutions (obtained by NMR and EPR spectroscopies and by potentiometric titrations),11,16,20,48 which showed that the freeze-dried samples used in this work maintained the speciation of V(V/IV) reaction products that were formed in solutions.
Treatments of any of A–D under simulated gastric conditions in the presence of food components ("liquid breakfast", see ESI;† samples A3–D3 in Table 1) resulted in the formation of the same product, as shown in the XANES of Fig. 1, 2 and Fig. S1d (ESI†). Since the differences in XANES obtained amongst conditions A3–D3 were comparable to the experimental noise levels (Fig. S1e, ESI†), the average of these data was used for further processing (Fig. 3c). The edge and post-edge shapes for A3–D3 were close to those for [VIII(OH2)6]3+ (H in Chart 1),33 while the pre-edge intensity was close to that for [VIVO(OH2)5]2+(B in Chart 1), as shown in Fig. 3c. Clear separation of A3–D3 from all the other samples on the basis of XANES parameters is evident in Fig. 2b. The best match for XANES of A3–B3 was with a combination of the XANES from models B, H, and I (V(IV) picolinato complex, Chart 1; a model of V(IV)-amino acid or protein binding),26–28 as shown in Table 1 and in Fig. S2 (ESI†). These results show that V(III) species can be formed by reduction of either V(V) or V(IV) in acidic medium of the stomach in the presence of organic reductants (food components).
A summary of likely chemical transformations of anti-diabetic V(V/IV) complexes in gastrointestinal media, deduced from XANES spectra (Table 1), is shown in Scheme 1. The most striking result of these studies was the crucial role of the presence and composition of food components on V speciation. According to the results of phase 1 human clinical trials, V absorption from oral administration of 75 mg of V(IV)–ethylmaltolato complex (a close analogue of C) was ∼13-fold higher in the fasted state compared with the fed state.1 These data pointed to a low bioavailability of V(IV) complexes with combinations of hydroxido, alcoholato and/or carboxylato ligands that were likely to form in the intestines in the presence of food components (Scheme 1). These can form due to the high thermodynamic stabilities of V(V/IV) 2-hydrocarboxylato donor groups that can form monomeric and polynuclear complexes, while the formation of V(V/IV) 1,2-diolato complexes with carbohydrates is unlikely under biological conditions.52,53 Such 1,2-diolato complexes require strongly basic conditions to form in solution from reactions of V(V) or V(IV) with sugars.52 As is the case for Cr(IV), V(IV) requires 2-hydroxyacid groups rather than simple diols to stabilize this oxidation state under physiologically relevant conditions.53 Apart from small molecule ligands, sialoglycoproteins may also provide donor groups for strong V(V/IV) binding.54 The bioavailability of V-containing drugs is expected to decrease further if the consumed food is rich in strong reductants, such as ascorbate,55,56 as demonstrated by comparison of digestion products in the presence of two types of semi-synthetic meals (samples A4, C4, A5, C5 in Table 1; see ESI† for meal composition).
Scheme 1 Proposed biotransformations of complexes A–D (Chart 1) in gastrointestinal environments based on the analyses of XANES data (Table 1).
The usefulness of three-dimensional correlations of XANES parameters that were developed previously22 for the determination of oxidation states and coordination numbers of V in complex matrices has been confirmed in the current study (Fig. 2). However, caution is required when the samples are likely to contain V in various oxidation states, such as A3–D3, A5 and C5 (Table 1 and Fig. 2). Therefore, the initial assessment of the chemical state of V with the use of the diagrams in Fig. 2 has to be complemented by comparison of whole XANES spectra of the samples with those of model complexes (Fig. 3, Fig. S1 and S2, ESI†). On the whole, these data confirm the previous findings14,15 that metal-based anti-diabetics are likely to undergo complete chemical rearrangement in gastrointestinal media, particularly in the presence of food components. The current studies have enabled all oxidation states to be studied in the one experiment, which was not possible in previous studies and has provided many new insights in the speciation that is important in understanding efficacy and safety of V anti-diabetics. These changes determine the mode of gastrointestinal absorption and further metabolism of these drugs and have rationalized the differences in in vivo efficacies. Reactivity of oral V(V/IV) anti-diabetics in gastrointestinal media has to be taken into account when considering their further reactions in the blood,66 and the current work provides an entry point for such studies, which will be reported in the future.67 The current work illustrates how the XANES methodologies described herein can be used in studies of vanadium speciation in blood,18,67 and also in cells,18,68 and tissues.
While the importance of V speciation in controlling the activities of biological systems has been recognised for many years,69 the XANES results reported herein provide the most definitive studies to date on the speciation of all oxidation states vanadium under conditions that mimic oral administration. Typical anti-diabetic V(V) and V(IV) complexes undergo profound chemical changes in gastrointestinal media, including dissociation of the ligands, V(IV) oxidation to V(V) (in the absence of food), or V(V) reduction to V(IV) and even V(III) (in the presence of food). Formation of V(III) may be important for further metabolism via Fe(III) pathways, but the main absorption mechanisms appear to be associated with vanadate (poorly absorbed), VIVO2+ species via M2+ uptake mechanisms, and passive diffusion of neutral species. These data confirm the role of such complexes as pro-drugs that release the active components on the interactions with biological media. Three-dimensional diagrams of pre-edge and edge parameters in XANES spectra, developed on the basis of a library of model V(V/IV/III) complexes,22 have proven to be useful for the assessment of the chemical states of V in biological environments.
The research was supported by Australian Research Council (ARC) Discovery Grants (DP0208409, DP0774173, DP0984722, DP1095310, and DP130103566), ARC Professorial Fellowships (DP0208409 and DP0984722) to P.A.L., and an ARC Linkage Infrastructure, Equipment and Facilities (LIEF) Program grant (LE0346515) for the 36-pixel Ge detector at ANBF. Initial X-ray absorption spectroscopy was performed partially at ANBF with support from the Australian Synchrotron Research Program (ASRP), which was funded by the Commonwealth of Australia under the Major National Research Facilities program (ANBF was operated by the Australian Synchrotron (AS) from 2009 until its closure in 2013). We acknowledge the LIEF program of the ARC for financial support (grant numbers LE0989759 and LE110100174) and the High Energy Accelerator Research Organisation (KEK) in Tsukuba, Japan, for operations support. We thank Drs Garry Foran, James Hester, Celesta Fong and Michael Cheah for the assistance with XAS experiments at ANBF, and Drs Glyn Devlin and Peter Kappen for those at the AS.
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 V. 
 V. 
 V. 
 V.