Serum Folate: A Pharmacodynamic Biomarker of Intracellular Nitrosylcobalamin Activity Following Intravenous Administration in Dogs
apo2l/trail; biomarker; cells; cobalamin; disease; dogs; Folate; homocysteine; methylmalonic acid; nitric-oxide; Nitrosylcobalamin; Oncology; pharmacokinetics; supplementation; suppression; vitamin B-12; vitamin B-12
Background/Aim: Cobalamin and folate are interdependent co-factors of the methionine synthase pathway. This study evaluated the effect of intravenously-administered nitrosylcobalamin (NO-Cbl), a vitamin B12 analog, on serum folate concentrations in healthy dogs. Materials and Methods: Four dogs received a 10-mg/kg, 20-mg/kg and 40-mg/kg intravenous bolus dose of NO-Cbl, with a 14-day washout period between doses. Blood samples were collected at baseline and post-dosing, and serum cobalamin and folate concentrations were measured. Results: For each dose, serum cobalamin concentrations were inversely correlated with serum folate concentrations. Spearman rank correlation coefficient values were -0.976 (10 mg/kg, p<0.0096), and -1.0 (20 mg/kg, p<0.008; 40 mg/kg, p<0.0046). Conclusion: Cellular uptake of NO-Cbl, following intravenous administration exerted a biological effect on folate similar to that previously described for other vitamin B12 analogs. Serum folate concentration may serve as a pharmacodynamic biomarker of intracellular nitrosylcobalamin activity following intravenous administration.
Sysel A M; Horne W I; Steiner J M; Suchodolski J S; Bauer J A
Anticancer Research
2012
2012-10
Journal Article
n/a
Pharmacokinetics of Intravenous Nitrosylcobalamin, an Antitumor Agent, in Healthy Beagle Dogs: A Pilot Study
apo2l/trail; canine organs; cobalamin; cobalamin vitamin-b-12; dogs; intravenous; nitric-oxide; Nitrosylcobalamin; Oncology; pharmacokinetics; protein; release; suppression; transcobalamin-ii; transport; vitamin B-12
Background/Aim: Nitrosylcobalamin (NO-Cbl) is a cobalamin-based anti-tumor agent. This study evaluated the pharmacokinetic parameters of NO-Cbl following intravenous administration in dogs. Materials and Methods: Four dogs received 10 mg/kg, 20 mg/kg and 40 mg/kg intravenous bolus doses of NO-Cbl, with a 14-day washout period between doses. Blood samples were collected at baseline and post-dosing, and noncompartmental pharmacokinetic parameters were determined. Results: Average peak serum concentrations of 2265, 5523 and 13,866 pg/mL were achieved following single-dose bolus intravenous administration of 10 mg/kg, 20 mg/kg and 40 mg/kg of NO-Cbl respectively. The average area under the curve was 12,697 h x pg/mL, 24,497 h x pg/mL and 44,976 h x pg/mL respectively, with an average elimination half-life of 16.2 h, 13.5 h and 13.1 h respectively. Conclusion: These results can be used to determine the dose and dosing intervals for clinical trials evaluating NO-Cbl in humans and companion animals.
Sysel A M; Horne W I; Steiner J M; Suchodolski J S; Bauer J A
Anticancer Research
2012
2012-09
Journal Article
n/a
Vitamin B-12 and Redox Homeostasis: Cob(II)alamin Reacts with Superoxide at Rates Approaching Superoxide Dismutase (SOD)
binding; chaperone; Chemistry; cobalamin; free-radicals; mechanism; nitric-oxide; oxidation; state
We report a kinetic study of the reaction between superoxide and an important intracellular form of vitamin B-12, cob(II)alamin. Superoxide is implicated in the pathophysiology of many inflammatory diseases, whereas vitamin B,2 derivatives are often beneficial in their treatment. We found that cob(II)alamin reacts with superoxide at rates approaching those of superoxide dismutase itself, suggesting a probable mechanism by which vitamin B-12. protects against chronic inflammation and modulates redox homeostasis.
Suarez-Moreira E; Yun J; Birch C S; Williams J H H; McCaddon A; Brascht N E
Journal of the American Chemical Society
2009
2009-10
Journal Article
<a href="http://doi.org/10.1021/ja904670x" target="_blank" rel="noreferrer noopener">10.1021/ja904670x</a>