Mercapturic acid formation during the metabolism of arecoline and arecaidine in the rat

1. In the rat, arecoline is converted into arecaidine and both compounds are converted into N-acetyl-S-(3-carboxy-1-methylpiperid-4-yl) -l-cysteine. 2. The structure of the metabolite was established by (a) synthesis, (b) conversion into N-acetyl-S-(3-methoxycarbonyl-1-methylpiperid-4-yl) -l-cysteine methyl ester, which was chromatographically identical with the synthetic material, and (c) n.m.r.-and i.r.-spectral analysis of the 3-methoxycarbonyl derivative. 3. In ethanolic solution, or in phosphate buffer at pH7.0, arecoline reacted with N-acetyl-l-cysteine to give N-acetyl-S-(3-methoxycarbonyl-1-methylpiperid-4-yl) -l-cysteine; under similar conditions, arecaidine reacted more slowly to give N-acetyl-S-(3-carboxy-1-methylpiperid-4-yl) -l-cysteine. 4. The reaction between arecoline and glutathione or N-acetyl-l-cysteine occurred maximally at neutral pH and decreased rapidly with increasing acidity. At neutral pH, the reactions were bimolecular and second-order when the reactants were in approximately equimolar concentrations and pseudo-unimolecular first-order when arecoline was in large excess. 5. Consideration of the pK(a) values and degrees of ionization of the reactants and the effect of pH on the stoicheiometry of reaction between arecoline and glutathione or N-acetyl-l-cysteine indicated that reaction between un-ionized species occurred more readily than nucleophilic addition (Ad(N)) reactions involving charged intermediates.