Bast A, Valk A J, Timmerman H
Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
Agents Actions. 1990 Apr;30(1-2):161-5. doi: 10.1007/BF01969027.
A series of diphenhydramine analogues have been studied with regard to their formation of a metabolic intermediate (MI) during their biotransformation in phenobarbital induced rat hepatic microsomes. The MI forms a complex with reduced cytochrome P-450. MI complexation of cytochrome P-450 may result in drug-drug interactions and/or in cumulation of the parent compound. The extent of MI complex formation could be correlated with the lipophilicity of the substrates in a parabolic manner. A hydrophobic pocket of limited dimensions in cytochrome P-450 for the N-alkyl substituent of the substrates can be assumed. Moreover our data indicate a role for the O-atom in the diphenhydramine analogues for the interaction with cytochrome P-450.
一系列苯海拉明类似物已针对它们在苯巴比妥诱导的大鼠肝微粒体生物转化过程中代谢中间体（MI）的形成进行了研究。该MI与还原型细胞色素P-450形成复合物。细胞色素P-450的MI络合可能导致药物相互作用和/或母体化合物的蓄积。MI复合物形成的程度可以以抛物线方式与底物的亲脂性相关。可以假定细胞色素P-450中存在一个尺寸有限的疏水口袋用于底物的N-烷基取代基。此外，我们的数据表明苯海拉明类似物中的O原子在与细胞色素P-450相互作用中起作用。
