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.

RETRACTED ARTICLE: Neuropathological and neuroprotective features of vitamin B12 on the dorsal spinal ganglion of rats after the experimental crush of sciatic nerve: an experimental study

“…In our study, vit B 12 had not remarkable affect on neurons at low - dose concentrations, especially with low-dose administration or short time, because the concentration of vit B 12 declines immediately [39] and the absorption of vit B 12 from the ileum and entire intestine is regulated by limitation of binding to gastric intrinsic factor and passive diffusion [40,41]. From the results of our study, we consider that it is necessary to devise new clinical methods, such as high-dose systemic or long time, to deliver high doses of vit B 12 to target organs to treat nervous disorders more effectively.…”

Inhibition of Hyperpolarization-Activated Cation Current in Medium-Sized DRG Neurons Contributed to the Antiallodynic Effect of Methylcobalamin in the Rat of a Chronic Compression of the DRG

“…It was suggested that MeCbl inhibited the increased excitability of medium-sized DRG neurons in CCD rats. The half-life of vitamin B12 in serum ranges from approximately 20 to 50 min, and one administration may not maintain a high concentration of vitamin B12 [ 47 ]. Therefore, to maintain the serum concentration of vitamin B12 to some extent, we continuously administered a higher dose.…”

Water‐Soluble Vitamins in People with Low Glomerular Filtration Rate or On Dialysis: A Review

“…In North Americans, the prevalence of vitamin B12 deficiency was 3% of those aged 20-39 years, 4% of those aged 40-59 years, and 6% of persons aged ! 60 years (86). Marginal deficiency was more common and occurred in 14-16% of those aged 20-59 years and 20% of those !…”

“…The current definition of vitamin B12 sufficiency is a serum level >210 pmol/l. This definition is based on the analysis of the NHANES cohort and represents the 95th percentile for vitamin B12‐replete subjects .…”