Studies on the in vivo biotransformation of the tobacco alkaloid beta-nicotyrine

This paper reports the results of studies on the in vivo metabolic fate of the tobacco alkaloid 1-methyl-2-(3-pyridinyl)pyrrole (beta-nicotyrine) in N ew Zealand white rabbits. Two previously characterized metabolites, 5-hydro xy-1-methyl-5-(3-pyridinyl)-2-pyrrolidinone (5-hydroxycotinine) and 2-hydro xy-1-methyl-5-(3-pyridinyl)-3-pyrrolin-2-one, were present in low concentra tions in the urine of the treated animals. The major urinary metabolite of beta-nicotyrine was identified as cis-3'-hydroxy-1-methyl-5-(3-pyridinyl)-2 -pyrrolidinone (cis-3'-hydroxycotinine), the diastereoisomer of the major u rinary metabolite of (S)-nicotine. The pathway leading to cis-3'-hydroxycot inine is proposed to proceed via autoxidation of 2-hydroxy-1-methyl-5-(3-py ridinyl)pyrrole, a postulated cytochrome P450-generated metabolite of beta- nicotyrine, followed by reduction of the carbon-carbon double bond present in the resulting 3-hydroxy-3-pyrrolin-2-one species. This proposal is suppo rted by the in vivo biotransformation of 2-acetoxy-1-methyl-5-(3-pyridinyl) pyrrole, a latent form of the putative hydroxypyrrole intermediate, to cis- 3'-hydroxycotinine. The in vivo conversion of 5-hydroxy-1-methyl-5-(3-pyrid inyl)-3-pyrrolin-2-one to 5-hydroxycotinine is offered as evidence that sup ports the proposed reduction step.