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Metabolic Interconversion of Acid Metabolites of Cotinine In Vitro

The in vitro metabolism of 4-(3-pyridyl)-4-oxo-butyric acid (POBA), 4-(3-pyridyl)-4-hydroxy-butyric acid (PHBA) and 5-(3-pyridyl)-tetrahydrofuranone-2 (PTHF) by hepatic fractions from different experimental animal species (rat, rabbit, hamster, guinea-pig) was studied. The results show that POBA can be reduced to PHBA followed by cyclisation to PTHF by enzymes present in the cell soluble fraction. Conversely PHBA can be oxidised to POBA in vitro by microsomal enzymes. The metabolic transformations observed are predominantly catalysed by enzymes. PTHF is transformed to PHBA by a chemical hydrolytic reaction which is enhanced by both microsomal and soluble enzymes. Under our HPLC analytical conditions, neither 3-pyridylacetic acid nor 4-(3-pyridyl)-butyric acid were detected. Among the four species studied, there was a significant difference in the reduction of POBA to PHBA, with rabbit and hamster having the stronger activity. When the three compounds were incubated with hepatic tissue from rats induced separately with phenobarbitone (PB), beta-naphthoflavone (beta NF) or arochlor-1254 (A-1254), no difference in interconversion of the metabolites was observed when compared to non-induced rats. Therefore, it is suggested that these interconversions of the compounds are probably not mediated by cytochrome-P450 isoenzymes. A consideration of the ratios of individual processes leads us to believe that the conversion of POBA to PHBA is on the major pathway in the degradation of continine to 3-pyridylacetic acid.