Pyridoxine (vitamin B6), a water-soluble vitamin, is administered as an antidote for overdoses of isonicotinic acid hydrazide (isoniazid, INH), Gyromitra esculenta mushrooms, hydrazine, methylated hydrazines, and ethylene glycol. With the exception of ethylene glycol, all of these xenobiotics produce seizures by the competitive inhibition of pyridoxal-5′-phosphate (PLP). Pyridoxine overcomes this inhibition and may also enhance the less-toxic pathway of ethylene glycol metabolism to form benzoic and hippuric acid, instead of oxalic acid.6 Hydrazine and methylated hydrazines (1,1-dimethylhydrazine [UDMH], monomethylhydrazine [MMH]) are used as rocket fuels, and MMH is also found in Gyromitra esculenta mushrooms.3
Pyridoxine deficiency characterized by seborrheic dermatitis, cheilosis, stomatitis, and glossitis was first identified in 1926 but was mistakenly attributed to the absence of vitamin B2 (see Chap. 41).31 Ten years later, the deficiency was fully characterized and correctly recognized as a deficiency to vitamin B6.31 A rare genetic abnormality that produced pyridoxine-responsive seizures in newborns was first described in 1954.5
The active form of pyridoxine is PLP.31 The alcohol pyridoxine, the aldehyde pyridoxal, and the aminomethyl pyridoxamine are all naturally occurring, related compounds that are metabolized by the body to PLP.31 Pyridoxine was chosen by the Council on Pharmacy and Chemistry to represent vitamin B6.31 Pyridoxine hydrochloride was chosen as the commercial preparation because of its stability.53
Pyridoxal-5′-phosphate is an important cofactor in more than 100 enzymatic reactions, including decarboxylation and transamination of amino acids, and the metabolism of tryptophan to 5-hydroxytryptamine [serotonin] and methionine to cysteine.23,31 Iatrogenic pyridoxine deficiency in animals produces seizures associated with reduced brain concentrations of PLP, glutamic acid decarboxylase, and γ-aminobutyric acid (GABA).16
Pyridoxine is not protein bound, has a volume of distribution of 0.6 L/kg, and easily crosses cell membranes; in contrast, PLP is nearly entirely plasma protein bound and essential for the synthesis and metabolism of GABA.53 At extrahepatic sites pyridoxine is rapidly metabolized to pyridoxal, PLP, and 4-pyridoxic acid, with only 7% excreted unchanged in the urine.53 After intravenous infusion of 100 mg of pyridoxine over 6 hours, PLP concentration increases rapidly in serum and in erythrocytes.53 Pyridoxal-5'-phosphate rises from 37 nmol/L to 2183 nmol/L in serum and from undetectable to 5593 nmol/L in erythrocytes, with peak concentrations achieved at the end of the infusion.53 Oral pyridoxine, in doses of 600 mg, is 50% absorbed within 20 minutes of ingestion by a first-order process with rapid achievement of peak serum concentrations of pyridoxine, PLP, and pyridoxal.52 The concentration of PLP appears to be tightly controlled in the serum and related to alkaline phosphatase activity.24,52 Oral doses of pyridoxine from 10 to 800 mg result in PLP concentrations of 518 to 732 nmol/L 4 hours after ingestion.52 Chronic alcoholic patients have lower baseline serum PLP concentrations, as acetaldehyde enhances the ...