Studies of cobalamin as a vehicle for the renal excretion of cyanide anion.
To examine the ability of hydroxocobalamin (vitamin B12a, HO-Cbl) to counteract the toxicity of cyanide by promoting the renal excretion of cyanide anion, we studied the pharmacokinetics of HO-Cbl and cyanocobalamin (vitamin B12, CN-Cbl) given in high doses to dogs. After administration of intravenous bolus doses of HO-Cbl and CN-Cbl (5, 10, 25 mg/kg) to female foxhounds, peak plasma concentrations were attained within 1 minute, after which the cobalamins disappeared from plasma in a manner consistent with two-phase distribution and elimination kinetics. While mean t1/2 measurements for the initial distribution phase were similar for HO-Cbl and CN-Cbl, the secondary excretion phase was more prolonged for HO-Cbl than for CN-Cbl (t1/2, 94.75 minutes vs 62.64 minutes, respectively). Pharmacokinetic data permitted the design of a HO-Cbl infusion schedule that resulted in stable plasma concentrations in test animals. When NaCN was then given intravenously to animals preloaded with HO-Cbl (20 micrograms/ml plasma), conversion of HO-Cbl to CN-Cbl in vivo, was documented by both thin-layer and high-performance liquid chromatographic analysis of successive urine samples. Moreover, in dogs preloaded with HO-Cbl (20 micrograms/ml plasma), up to 10% of the cyanide administered as NaCN infusions was recovered in urine as CN-Cbl by 60 minutes, compared with less than 0.3% in dogs not treated with HO-Cbl. In addition, under these conditions of HO-Cbl loading, the minimum doses of NaCN required to produce sublethal signs of cyanide toxicity (hypotension, tachypnea, tachycardia) were found to be increased to levels that in some cases exceeded normally lethal doses.(ABSTRACT TRUNCATED AT 250 WORDS)
Williams
H L
HL
Department of Hematology, Walter Reed Army Institute of Research, Washington, DC 20307-5100.
Johnson
D J
DJ
McNeil
J S
JS
Wright
D G
DG
D000818:Animals; D000931:Antidotes; D003486:Cyanides / Q000493:pharmacokinetics / Q000633:toxicity*; D004285:Dogs; D005260:Female; D006879:Hydroxocobalamin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D007668:Kidney / Q000378:metabolism*; D014805:Vitamin B 12 / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*
D000931:Antidotes; D003486:Cyanides; D014805:Vitamin B 12; D006879:Hydroxocobalamin