THE METABOLISM OF BETAHISTINE IN THE RAT

The metabolism of betahistine, 2-(2-methylaminoethyl)pyridine, a bio-isostere of histamine, was studied in the rat. 2-Pyridylacetic acid, which had been previously isolated as a metabolite of betahistine from dog and rabbit urine, was isolated from rat urine as well as from rat liver homogenates. In addition, trace amounts of the N-demethylated product, 2-(2-aminoethyl)pyridine, was isolated from liver homogenates. In vitro studies revealed that the preponderance of betahistine oxidase activity originated in liver mitochondria and was attributable to monoamine oxidase (MAO). The participation of mitochondrial MAO in metabolism was corroborated by inhibiting betahistine oxidation with specific MAO inhibitors. Additional experiments ruled out the involvement of diamine oxidase in betahistine metabolism. The kinetics for the MAO-catalyzed oxidation of betahistine was studied and revealed that betahistine had a greater affinity for mitochondrial MAO (KM = 3.3 x 10-5 M) than did tyramine, serotonin, or benzylamine.