Seidegård J, Grönquist L, Gunnarsson P O
Department of Pharmacokinetics, Pharmacia LEO Therapeutics AB, Helsingborg, Sweden.
Biochem Pharmacol. 1990 May 1;39(9):1431-6. doi: 10.1016/0006-2952(90)90424-j.
A novel nitrosourea, 1-(2-chloroethyl)-3-[2-(dimethylaminosulphonyl)ethyl]1-nitrosourea , tauromustine (TCNU), has been investigated for in vitro metabolism by different rat organs. Two kinds of reactions were seen, demethylation and denitrosation, both reactions required NADPH. These reactions were achieved by the liver microsomes and to a much lesser extent by lung microsomes. Induction of cytochrome P450 system with phenobarbital resulted in increased demethylation (10 times) and denitrosation (6 times) of tauromustine while induction with 3-methylcholanthrene did not have any significant effect on these reactions. Known inhibitors of different cytochrome P450 activities inhibited the demethylation and denitrosation of tauromustine to different levels. After oral administration of [14C]tauromustine a metabolic pattern similar to that observed in vitro experiments, was seen in the urine. The demethylated compound, which has alkylating cytotoxic activity, could be detected in the urine up to 8 hr after oral administration.
一种新型亚硝基脲，1-(2-氯乙基)-3-[2-(二甲基氨基磺酰基)乙基]-1-亚硝基脲，即牛磺莫司汀（TCNU），已被研究其在不同大鼠器官中的体外代谢情况。观察到两种反应，即去甲基化和脱亚硝基化，这两种反应都需要NADPH。这些反应由肝微粒体完成，肺微粒体的作用程度则小得多。用苯巴比妥诱导细胞色素P450系统会导致牛磺莫司汀的去甲基化（增加10倍）和脱亚硝基化（增加6倍），而用3-甲基胆蒽诱导对这些反应没有任何显著影响。已知的不同细胞色素P450活性抑制剂会将牛磺莫司汀的去甲基化和脱亚硝基化抑制到不同程度。口服[14C]牛磺莫司汀后，尿液中出现了与体外实验中观察到的类似代谢模式。具有烷基化细胞毒性活性的去甲基化化合物在口服后8小时内都能在尿液中检测到。
