Preparation and characterization of vanadyl complexes with bidentate maltol-type ligands; in vivo comparisons of anti-diabetic therapeutic potential.
A series of 2-alkyl-3-hydroxy-4-pyrone oxovanadium(IV) compounds has been synthesized, characterized, and tested for bioactivity as potential insulin-enhancing agents. The vanadyl complexes, bis(maltolato)oxovanadium(IV), BMOV, bis(ethylmaltolato)oxovanadium(IV), BEOV, and bis(isopropylmaltolato)oxovanadium(IV), BIOV, were compared against vanadyl sulfate for glucose-lowering ability, when administered i.p. to STZ-diabetic rats, at a one-time dose of 0.1 mmol kg(-1)body weight. Blood levels of vanadium were determined at regular intervals, to 72 h, following i.p. injection. All complexes tested exceeded vanadyl sulfate in glucose-lowering ability; this effect was not correlated, however, with blood vanadium levels. Analysis of the pharmacokinetics of the disappearance of [ethyl-1-(14)C]BEOV after an oral gavage dose (50 mg kg(-1), 0.144 mmol kg(-1), in a 10 mL kg(-1) volume of 1% CMC solution) indicated clearly that metal ion-ligand dissociation took place relatively soon after oral ingestion of the complex. Half-lives of fast phase uptake and slow phase disappearance for (14)C and V were calculated from a two-compartment model for whole blood, plasma, liver, kidney, bone, small intestine, and lung, ranging from 17 min ( t(1/2)alpha for (14)C, liver) to 30 days ( t(1/2)beta for V, bone). Curves of disappearance of plasma and whole blood (14)C and V diverged dramatically within the first hour after administration of the vanadium complex.
Thompson
Katherine H
KH
Department of Chemistry, The University of British Columbia, 2036 Main Mall, Vancouver, BC, V6T 1Z1, Canada, kthompso@chem.ubc.ca
Liboiron
Barry D
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Sun
Yan
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Bellman
Karycia D D
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Setyawati
Ika A
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Patrick
Brian O
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Karunaratne
Veranja
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Rawji
Gulnar
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Wheeler
Jeffrey
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Sutton
Kymberley
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Bhanot
Sanjay
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Cassidy
Carrie
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McNeill
John H
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Yuen
Violet G
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Orvig
Chris
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D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002250:Carbon Radioisotopes; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D005260:Female; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D008024:Ligands; D008958:Models, Molecular; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014639:Vanadium / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D017968:Vanadium Compounds / Q000494:pharmacology
D001786:Blood Glucose; D002250:Carbon Radioisotopes; D007004:Hypoglycemic Agents; D008024:Ligands; D009942:Organometallic Compounds; D017968:Vanadium Compounds; D014639:Vanadium; C034028:vanadyl sulfate