Cooper R G, Evans D A, Price A H
Department of Medicine, University of Liverpool, U.K.
Eur J Clin Pharmacol. 1987;32(6):569-76. doi: 10.1007/BF02455990.
We have studied the disposition of perhexiline and its two major metabolites, M1 and M3, in healthy volunteers and in patients with biliary T-tube drains after cholecystectomy. In healthy volunteers the genetic control for impaired hepatic oxidation is identical for debrisoquine, sparteine, and perhexiline. Poor metabolizers demonstrate markedly reduced production and excretion of the major metabolite, M1. Their production of M3 is also reduced, but to a lesser degree than for M1, confirming substrate stereoselectivity by hepatic oxidases. Biphasic urinary elimination of M1 and M3 is seen in intact extensive oxidizers, whereas only the first phase is apparent in patients with biliary T-tube drainage. This suggests the possibility of enterohepatic recycling of these compounds, which may account for their prolonged elimination. More than 90% of an ingested dose of perhexiline maleate remains unaccounted for at 24 h after ingestion, even in extensive metabolizers. A careful, radiolabelled tissue-distribution study is warranted to elucidate the complicated metabolic fate of perhexiline.
我们研究了哌克昔林及其两种主要代谢产物M1和M3在健康志愿者以及胆囊切除术后带有胆汁T形管引流的患者体内的处置情况。在健康志愿者中，对于异喹胍、司巴丁和哌克昔林，肝脏氧化受损的遗传控制是相同的。代谢缓慢者体内主要代谢产物M1的生成和排泄显著减少。他们体内M3的生成也减少，但程度小于M1，这证实了肝脏氧化酶的底物立体选择性。在完整的氧化代谢快的个体中，M1和M3的尿排泄呈双相，而在有胆汁T形管引流的患者中仅出现第一相。这表明这些化合物存在肠肝循环的可能性，这可能是它们消除时间延长的原因。即使是氧化代谢快的个体，摄入马来酸哌克昔林剂量的90%以上在摄入后24小时仍无法解释去向。有必要进行一项细致的放射性标记组织分布研究，以阐明哌克昔林复杂的代谢命运。
