title: Pharmacokinetics of high doses of cyanocobalamin administered by intravenous injection for 26 weeks in rats.
abstract: 1. High doses of vitamin B12 (cyanocobalamin) may be therapeutically effective to treat neurological alterations secondary to a wide range of disease states. The aim of the present study was to evaluate the effect of dose and repeated administration on the pharmacokinetics of cyanocobalamin in rats. 2. Forty-eight rats were randomly assigned to receive 1, 5, 25 or 100 mg/kg cyanocobalamin for 182 days (26 weeks). Cyanocobalamin plasma levels were quantified by HPLC on days 1, 85 and 182 of treatment and were analysed by means of non-compartment pharmacokinetic (PK) analysis. In addition, population PK analysis was used to fit cyanocobalamin plasma concentrations to time by means of a two-compartment model for intravascular administration. 3. The half-life of cyanocobalamin ranged from approximately 20 to 50 min, clearance ranged from 4.5 to 9 mL/min and the volume of distribution at steady state ranged from 140 to 470 mL. A statistically significant negative relationship existed between the dose of cyanocobalamin and the normalized area under the plasma concentration-time curve (AUC). This non-linearity was not exhibited in population PK analysis. No evidence of toxicity was observed. 4. At very high and prolonged doses (up to 100 mg/kg for 26 weeks), intravascular administration of cyanocobalamin in rats follows a two-compartment kinetic model and cyanocobalamin undergoes extensive extravascular distribution. The negative relationship between dose and normalized AUC is compatible with possible saturation of tubular reabsorption, thus increasing renal clearance at higher doses.
authors.affiliation: Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, Canada. navaocampo_aa@yahoo.com
authors.forename: Alejandro A
authors.initials: AA
authors.lastname: Nava-Ocampo
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Pastrak
authors.forename: Tony
authors.initials: T
authors.lastname: Cruz
authors.forename: Gideon
authors.initials: G
authors.lastname: Koren
mesh_terms: D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006397:Hematinics / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D008297:Male; D015233:Models, Statistical; D051381:Rats; D017207:Rats, Sprague-Dawley; D014805:Vitamin B 12 / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D006397:Hematinics; D014805:Vitamin B 12