US 5,030,676 UV stabilized pvc

Abstract

The availability of a sensitive analytical assay for the simultaneous quantitation of pargyline (PARG) and four of its major metabolites have made possible a detailed study on the metabolism of the drug in rat liver microsomes with emphasis put on comparisons between optional N-dealkylation reactions and N-oxide formation. Pargyline is a lipophilic amine with a low pKa-value of 6.6 and undergoes extensive metabolism. The conversion of the substrate is rapid and comprizes three N-dealkylation and one N-oxidation reactions, yielcling N-benzylpropargylamine (BPA), N-methyl-propargylamine (MPA), N-benzylmethylamine (BMA) and pargyline N-oxide (PNO), respectively. Phenobarbital (PB) pretreatment of the rats causes a pronounced increase in the metabolism with about 90% of the substrate being consumed within the first minute of incubation at 100 μM substrate concentration. At this substrate concentration the most pronounced induction is seen in the formation of BPA and also in its further metabolism, while levels of BMA and MPA remain fairly constant. Pargyline N-oxide is the most abundant metabolite in microsomes from untreated rats and its formation is not increased by PB induction. Moreover, the inhibition of PNO formation by typical cytochrome P-450 inhibitors is marginal, while that of BPA, BMA and MPA formation is not. N-Debenzylation, yielcling MPA, is the least important of the N-dealkylation reactions and the effect of PB induction on this reaction becomes noticeable only at high substrate concentrations. The studies suggest that various cytochrome P-450 enzymes are involved in the N-dealkylation reactions of PARG while N-oxidation appears to occur mainly by a cytochrome P-450-independent pathway. As propiolaldehyde, a potential hepatotoxin, is formed concomitant to BMA, and as PNO, under certain conditions, can decompose to acrolein, another well-known hepatotoxin, both these quantitatively important metabolic routes have to be considered in evaluating the toxicity of pargyline.