Table 1.

List of favorable/unfavourable arguments for the development of vanadium-containing oral antidiabetics.

Keywords	Comments	Ref.
Extensive chemical reactivity’s in body fluids	Vanadium shows a highly complex solution chemistry including changes of oxidation states, coordination number and geometries.	[20, 96-106]
Complex stability versus speciation	Speciation is a sort of biotransformation due to complex instabilities with subsequent chelator - bioligand interchange with the environment. Strikingly complex speciation pathways were described for the gastrointestinal tract, the blood stream as well as the pulmonary tract.	[38, 106-114]
Pharmacokinetics, metabolic properties	Analytical experiments have to study the in vivo behavior of the vanadium moieties in the body, considering that the original vanadium drug is converted into variable “metabolites” with changing composition by speciation.	[conclusions drawn by the authors]
Critical interactions with body components with key functions for living cells	Permeation of erythrocytes and binding to haemoglobin either by free species (VO2+) or the intact synthetic complex. In the blood serum plasma protein binding occurs with transferrin and to a lesser extent to albumin and immunoglobulin.	[38, 63, 115, 116]
Missing target specificities	Due to the high amino acid sequence conservation (homology) between target PTP1B and other PTPs, certain phosphatases are also targeted. In addition, the active form of the vanadium drugs which ultimately binds to PTP1B or others is still under debate. To complicate matter, reduction of vanadate to vanadyl in the cytoplasm gives rise to even more enzyme interferences. Conversely, administered vanadyl is the source supplying minute amounts of vanadate (IV) even without redox reactions.	[2, 21, 117]
Missing pathway selectivities	Phosphatases and kinases belong to two vast families of proteins, which are switched in large metabolic pathways, sometimes in key positions, sometimes with “sidewalks”. That said a range of (off-target) effects can be expected. Among desired and undesired side effects the following were reported: Leptin receptor, ATPase, PPARs agonist, AKT stimulation, AMPK activation, or the indirect stimulation of insulin secretion etc.	[20, 56, 117-122]
Defined structure-activity relationships	Due to the structural similarity natural phosphate anions must compete with oxidovanadate (V) which is a stronger binder. But vanadate occupies the active site much longer than phosphate what coined the more practical term of “irreversible binding” which leads to an effective enzyme blocking against weaker binding phosphates. Both, vanadate (V) and phosphate, coordinate into trigonal-bipyramidal complexes with five ligands. The penta-coordination at vanadium is a very stable geometry, while the fifth (covalent) bond is a quite instable transition state complex at the active sites for phosphate-dependent enzymes. The similarity to phosphate explains how vanadate irreversibly inhibits many phosphate-dependent enzymes, not only insulin-related protein tyrosine phosphatases, but also kinases, among others.	[123-127]
Interindividual variability in animal tests and patients	Variable bioavailability and pharmacological response between tested patients for vanadyl sulfate under oral doses of 1mM per day. Also in diabetic rats, oral bioavailability was very low and severe side effects observed under treatment with inorganic vanadium salts. As a direct result organic V complexes were proposed.	[26, 84, 128-133]
Uncontrolled daily intake	Food additives or nutritional supplements, water and air account for the daily supply of vanadium but most of it is eliminated due to poor oral absorption. For instance, peroxidovanadates show no oral bioavailability at all. The risk of adverse health effects (threshold) starts at intake levels over 10 mg per kg body weight for a person. Normal exposure to these natural sources is below that threshold. The process of body detoxification was described concerning chemical and biochemical aspects.	[21, 60, 134-137]
Ambient concentration	Drinking water and food together supply an average between 0.01 mg and 2 mg per day. Drinking (sea) water has a concentration of 10 (45) nM, respectively. The food contents ranges from 1 to 30 µg per kg food. Vanadium oxides are found in lower concentrations in the air of rural areas with roughly 1 ng per cubic meter up to 100 ng per cubic meter in cities.	[21, 38, 47, 121, 137]
Accumulation risk and chronic intoxication risk	An adult person stores roughly 1mg vanadium. Blood levels oscillate around 45 nM. Phosphate in bones (apatite: Ca5(PO4)3OH) is replaced for vanadate. Its half-life amounts to 30 days (residence time 5 days). Vanadium accumulates more in bones, followed by kidneys, then liver. It is feared that therapeutic doses overlap with lower toxic concentrations of 0.2 to 3 mM. For instance, vanadyl sulfate and ammonium metavanadate were administered in animal tests in doses between 0.1 to 0.7 mM per kg and day and 2 mmol (100 mg) per day. Acute lethal doses were measured as LD50 with 0.15 mM per kg body weight for sodium metavanadate. Later it was reported that thanks to the poor bioavailability (low absorption combined with high excretion rate in humans) toxic and therapeutic doses do not overlap.	[21, 102-109, 113, 138-144]
	High vanadium exposure shows effects on the immune system.	[81]
	Reactive oxygen species (ROS) were identified as problematic intermediates for vanadium metabolism.	[21]
Mutagenesis risk	RNA or DNA-related problems were also reported, e.g. binding to DNA primer during DNA polymerase activity. Certain vanadium complexes may act by DNA intercalation (with a potential benefit in antineoplastic, antitumor therapy).	[110]