Differential induction of 3-ethyl-2,6-dimethyl-4H-pyrido (1,2-alpha)pyrimidin-4-one metabolism by phenobarbital and 3-methylcholanthrene in microsomes and isolated perfused rat liver

1. The in vitro metabolism of 3-ethyl-2,6-dimethyl-4H-[2-14C]pyrido(1,2-alpha)pyrimidin-4-one (PYPY) was studied in liver microsomes and isolated perfused liver of 3-methylcholanthrene (MC) or phenobarbital (PB)-treated, and untreated rats. 2. Hydroxylation of the alkyl substituents was the main metabolic pathway for PYPY in both in vitro systems of untreated, and MC-treated animals, but with different proportions of the metabolites. PB enhanced the rate of ring hydroxylation, especially in the microsomes, and the product of this reaction became the main metabolite of PYPY biotransformation. Ring hydroxylation reactions in the microsomes and in the isolated perfused liver led to different products. 3. Differences arose in the rate of some oxidative reactions measured in the two in vitro systems resulting in altered metabolic patterns. PB enhanced not only quantitative but qualitative differences in the two systems. 4. The altered metabolite profile observed with whole liver compared with the products of microsomes, and the enhanced amount of water-soluble metabolites due to PB treatment in experiments with perfused liver indicate the involvement of further metabolic processes, perhaps conjugation reactions, in PYPY metabolism in the perfused liver. 5. The differences observed in the inducibility of some oxidative reactions by MC and PB indicate the involvement of at least three distinct cytochrome P-450 isozymes in the metabolism of PYPY.