Weli A M, Lindeke B
Biochem Pharmacol. 1985 Jun 1;34(11):1993-8. doi: 10.1016/0006-2952(85)90321-1.
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, yielding 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 microM 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, yielding 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.
一种能够同时定量测定帕吉林（PARG）及其四种主要代谢产物的灵敏分析方法，使得在大鼠肝微粒体中对该药物代谢进行详细研究成为可能，研究重点是比较选择性N-脱烷基化反应和N-氧化反应。帕吉林是一种亲脂性胺，其低pKa值为6.6，且会发生广泛代谢。底物的转化迅速，包括三个N-脱烷基化反应和一个N-氧化反应，分别产生N-苄基炔丙胺（BPA）、N-甲基炔丙胺（MPA）、N-苄基甲胺（BMA）和帕吉林N-氧化物（PNO）。用苯巴比妥（PB）预处理大鼠会导致代谢显著增加，在100微摩尔底物浓度下孵育的第一分钟内，约90%的底物被消耗。在此底物浓度下，BPA的形成及其进一步代谢中诱导作用最为明显，而BMA和MPA的水平保持相当恒定。帕吉林N-氧化物是未处理大鼠微粒体中最丰富的代谢产物，其形成不会因PB诱导而增加。此外，典型的细胞色素P-450抑制剂对PNO形成的抑制作用很小，而对BPA、BMA和MPA形成的抑制作用则不然。产生MPA的N-脱苄基化是N-脱烷基化反应中最不重要的，PB诱导对该反应的影响仅在高底物浓度时才明显。研究表明，各种细胞色素P-450酶参与了PARG的N-脱烷基化反应，而N-氧化似乎主要通过细胞色素P-450非依赖途径发生。由于与BMA同时形成的丙炔醛是一种潜在的肝毒素，并且在某些条件下PNO可分解为另一种著名的肝毒素丙烯醛，因此在评估帕吉林的毒性时必须考虑这两条在数量上很重要的代谢途径。
