Savenije-Chapel E M, Bast A, Noordhoek J
Eur J Drug Metab Pharmacokinet. 1985 Jan-Mar;10(1):15-20. doi: 10.1007/BF03189692.
Hydroxylated metabolites of diazepam can be conjugated and are therefore generally thought not to affect the metabolism of diazepam. Liver microsomes, obtained from phenobarbital-pretreated rats, showed an inhibition of diazepam (10(-5) M) metabolism by desmethyldiazepam as well as by N-methyloxazepam or oxazepam (5 X 10(-5) M). In a single-pass perfusion of the rat liver an inhibition of diazepam disposition by exogenously administered desmethyldiazepam and by hydroxylated diazepam metabolites was also demonstrated. No oxazepam glucuronides were found after oxazepam infusion. However, infusion with N-methyloxazepam resulted in large amounts of oxazepam-glucuronides. The results indicate that administration of N-demethylated as well as hydroxylated metabolites may result in inhibition of the metabolism of their precursor. If hydroxylated metabolites are formed in situ they become more easily conjugated in comparison with administered hydroxylated metabolites and are therefore less effective as inhibitor.
地西泮的羟基化代谢产物可发生结合反应，因此一般认为它们不会影响地西泮的代谢。从经苯巴比妥预处理的大鼠获得的肝微粒体显示，去甲地西泮以及N-甲基奥沙西泮或奥沙西泮（5×10⁻⁵ M）对10⁻⁵ M地西泮的代谢有抑制作用。在大鼠肝脏的单次灌注中，外源性给予的去甲地西泮和羟基化地西泮代谢产物对地西泮处置的抑制作用也得到了证实。奥沙西泮输注后未发现奥沙西泮葡糖醛酸苷。然而，输注N-甲基奥沙西泮会产生大量奥沙西泮-葡糖醛酸苷。结果表明，给予N-去甲基化代谢产物以及羟基化代谢产物可能会导致其前体代谢受到抑制。如果羟基化代谢产物在体内原位形成，与给予的羟基化代谢产物相比，它们更容易发生结合反应，因此作为抑制剂的效果较差。
