Meloche S, Besner J G
Drug Metab Dispos. 1986 Mar-Apr;14(2):246-9.
The biliary metabolites of isotretinoin were examined after iv administration of 4-20-mg/kg doses to vitamin A-normal bile duct-cannulated rats. Analysis of bile by reverse phase high performance liquid chromatography showed that injection of isotretinoin is followed by a rapid excretion of metabolites in bile. Isotretinoin glucuronide was identified as the major metabolite in bile. A specific high performance liquid chromatography method based on the assay of generated isotretinoin in beta-glucuronidase-treated bile was developed for the determination of isotretinoin glucuronide in bile samples. The excretion rate of isotretinoin glucuronide increased rapidly to reach a maximum 55 min after dosing and then declined exponentially. After 330 min of collection, biliary excretion of isotretinoin glucuronide was almost complete, and the metabolite accounted for 34.8-37.9% of the dose. These results indicate that conjugation with glucuronic acid represents a major pathway for the metabolism of pharmacological doses of isotretinoin. The maximum excretion rate of isotretinoin glucuronide in bile increased in a linear manner with the dose of isotretinoin, and no delay was observed after the larger doses. These data suggest that glucuronidation and biliary excretion are not saturated at high pharmacological doses of isotretinoin.
在给维生素A水平正常且胆管插管的大鼠静脉注射4 - 20毫克/千克剂量的异维A酸后，对其胆汁中的代谢产物进行了检测。通过反相高效液相色谱法对胆汁进行分析，结果显示注射异维A酸后，代谢产物在胆汁中迅速排出。异维A酸葡糖醛酸苷被确定为胆汁中的主要代谢产物。基于对β-葡糖醛酸酶处理后的胆汁中生成的异维A酸进行测定，开发了一种特定的高效液相色谱法，用于测定胆汁样本中的异维A酸葡糖醛酸苷。异维A酸葡糖醛酸苷的排泄率迅速上升，在给药后55分钟达到最大值，然后呈指数下降。收集330分钟后，异维A酸葡糖醛酸苷的胆汁排泄几乎完成，该代谢产物占给药剂量的34.8 - 37.9%。这些结果表明，与葡糖醛酸结合是药理剂量异维A酸代谢的主要途径。胆汁中异维A酸葡糖醛酸苷的最大排泄率随异维A酸剂量呈线性增加，较大剂量给药后未观察到延迟现象。这些数据表明，在高药理剂量的异维A酸作用下，葡糖醛酸化和胆汁排泄未达到饱和。
