Speciation of VIIV Complexes in Biological Fluids

Due to parallel protonation processes of the metal-binding sites of the coordinating ligands, these complexes certainly decompose in the acidic pH range, e.g. at the pH (~2) of the gastric juice. This is demonstrated in Figure 8.4, in

Figure 8.3 Plasma glucose levels for VIVO2+ (O), [VVO2(mal)2r (■), VIVO(mal)2 (•) and VIVO(kojic acid)2 (□) following acute (a) oral gavage administration to STZ-diabetic rats at a dose of 0.55 mmol kg-1 and (b) intraperitoneal injection in STZ-diabetic rats at a dose of 0.06 mmol kg-1 (Reproduced from Ref. 31 with permission from Elsevier)

Figure 8.3 Plasma glucose levels for VIVO2+ (O), [VVO2(mal)2r (■), VIVO(mal)2 (•) and VIVO(kojic acid)2 (□) following acute (a) oral gavage administration to STZ-diabetic rats at a dose of 0.55 mmol kg-1 and (b) intraperitoneal injection in STZ-diabetic rats at a dose of 0.06 mmol kg-1 (Reproduced from Ref. 31 with permission from Elsevier)

Figure 8.4 Species distribution curves for (a) VIVO-maltolato and (b) VIVO-picolinato systems as a function of pH, at 1:2 metal ion to ligand ratio, c(VIVO) = 1 mM (based on data reported in Refs 33-37)

which the species distribution in two well-studied systems, the VO(IV)-malto-lato and the VO(IV)-picolinato systems, is depicted as a function of pH.

Accordingly, all other exogenous and endogenous biomolecules present in the stomach or intestine, where the complexes are absorbed, may play a role in VO(IV) binding. This certainly has to be taken into account in the formulation of the drug (e.g. by encapsulation techniques, these problems may well be overcome). The recent results of Sakurai etal.32 support this prediction. After absorption, during their transport in the bloodstream, complex formation with the serum components as active VO(IV) binders also has to be considered. The interactions of several potential insulin-mimetic drugs with the high molecular mass (HMM) protein constituents, e.g. albumin and transferrin (Tf), and some of the LMM constituents (the most potent binders), e.g. lactate, phosphate, oxalate and citrate, have been studied in detail.33 41 The results of model calculations for serum conditions41 are depicted in Figure 8.5.

It can be seen in Figure 8.5 that (i) only the pyridinone derivative is a strong enough carrier to preserve a significant proportion of the VO(IV) in the original complex;37,39 in the other cases, the carrier ligands are displaced by serum components. Accordingly, the most important role of the carrier ligand seems to be to facilitate the absorption of VO(IV). Second, of the two important HMM binders, Tf is much more efficient than albumin and will displace 30-70% of the original carrier from the complex. (At the biologically more

[Image not available in this electronic edition.]

Figure 8.5 Speciation of various insulin-mimetic VO(IV) compounds (100 mM) in serum at pH 7.4 (mal: maltolate, pic: picolinate, Mepic: 6-Me-picolinate, hpo: 2-HO-pyridine-N-oxide, mpo: 2-HS-pyridine-N-oxide, hdp: 1,2-dimethyl-3-hydroxy-4-pyridinone) (based on data reported in Refs 33-37)

relevant VO(IV) concentrations (<5mM), practically all the VO(IV) is bound to Tf.) Third, among the LMM binders, citrate is the only 'active' component able to influence the solution state of these insulin mimetics. At physiological pH, VO(IV) exists mostly as the VO(IV) citrate binary complex and as the VO(IV) ligand A citrate mixed ligand complex, but in different proportions.

The decisive role of Tf in VO(IV) binding can be demonstrated by EPR. It has been found40 42 that in the presence of apoTf, all carrier complexes showed anisotropic EPR spectra even at room temperature (because of the slow tumbling motion of the VO(IV)-protein complex, the parallel and the perpendicular components could not be averaged), unambiguously indicating interactions between the carrier complex of VO(IV) and the protein. As seen in Figure 8.6, in the case of VO(pic)2, the RT spectrum is practically the same as that of VO(IV) apoTf, suggesting a complete displacement of the carrier ligand by Tf. At the same time, in the case of the VO(IV) (hdp)2 complex, signals of the anisotropic carrier complex can also be observed, suggesting only partial displacement of the carrier ligand. These results are in complete agreement with the species distributions depicted in Figure 8.5.

These results strongly indicate that vanadium must be released from the carrier compound in order for it to be pharmacologically active. Perhaps the most convincing point is the different pharmacokinetics of disappearance of vanadium and the carrier ligand.43 Although, in principle, the ligand should be present at roughly twice the concentration of vanadium in the blood, it is found to be present at a lower concentration compared with vanadium from the

270 320 370 420 H/mT

Figure 8.6 Room temperature EPR spectra of (a) VO(IV)(pic)2, (b) VO(IV)-apoTf, (c) VO(IV)(pic)2-apoTf, (d) VO(IV)(hdp)2-apoTf and (e) VO(IV)(hdp)2 at pH 7.4, hdp: 1,2-dimethyl-3-hydroxy-4-pyridinone

270 320 370 420 H/mT

Figure 8.6 Room temperature EPR spectra of (a) VO(IV)(pic)2, (b) VO(IV)-apoTf, (c) VO(IV)(pic)2-apoTf, (d) VO(IV)(hdp)2-apoTf and (e) VO(IV)(hdp)2 at pH 7.4, hdp: 1,2-dimethyl-3-hydroxy-4-pyridinone

1-hour time point onwards. Thus, a number of recent studies have demonstrated fairly conclusively that insulin-mimetic vanadium complexes dissociate rapidly once ingested or injected. In other words, the eventual in vivo metabolic fate for chelated vanadium complexes differs little, if at all, from that of non-complexed vanadium compounds, when they are administered orally.41

Was this article helpful?

0 0
10 Ways To Fight Off Cancer

10 Ways To Fight Off Cancer

Learning About 10 Ways Fight Off Cancer Can Have Amazing Benefits For Your Life The Best Tips On How To Keep This Killer At Bay Discovering that you or a loved one has cancer can be utterly terrifying. All the same, once you comprehend the causes of cancer and learn how to reverse those causes, you or your loved one may have more than a fighting chance of beating out cancer.

Get My Free Ebook


Post a comment