Lee F Y, Workman P, Cheeseman K H
Biochem Pharmacol. 1987 Apr 15;36(8):1349-55. doi: 10.1016/0006-2952(87)90093-1.
On the basis of promising experimental studies, the nitroimidazoles misonidazole (MISO) and benznidazole (BENZO) are under clinical investigation as chemosensitizers in combination with the chloroethylnitrosourea CCNU. We have shown previously that MISO and BENZO can alter the pharmacokinetics of CCNU leading to an improved therapeutic index in mice. Here we demonstrate using optical difference spectroscopy that MISO and BENZO are able to bind to cytochrome P-450 of mouse liver microsomes in vitro. Binding was type II in nature, indicating co-ordination of the free imidazole nitrogen with the heme moiety of cytochrome P-450. This results in an inhibition of CCNU hydroxylation by the hemoprotein. The kinetics of inhibition were of a mixed competitive-non-competitive type. At a CCNU concentration of 0.05 mM the concentrations causing 50% inhibition (I50) were 5.8 and 0.37 mM for MISO and BENZO respectively. At doses producing a similar improvement in therapeutic index in mice (2.5 mmoles/kg MISO and 0.3 mmoles/kg BENZO) the plasma and tissue concentrations achieved would inhibit CCNU hydroxylation by 30%. For BENZO, but not MISO, similar inhibition would also occur at concentrations which can be achieved safely in man.
基于前景良好的实验研究，硝基咪唑类药物米索硝唑（MISO）和苄硝唑（BENZO）正在作为化学增敏剂与氯乙基亚硝脲CCNU联合使用进行临床研究。我们之前已经表明，MISO和BENZO可以改变CCNU的药代动力学，从而提高小鼠的治疗指数。在此，我们使用光学差示光谱法证明，MISO和BENZO在体外能够与小鼠肝脏微粒体的细胞色素P-450结合。这种结合本质上属于II型，表明游离咪唑氮与细胞色素P-450的血红素部分配位。这导致血红蛋白对CCNU羟基化的抑制。抑制动力学属于混合竞争-非竞争类型。在CCNU浓度为0.05 mM时，MISO和BENZO引起50%抑制（I50）的浓度分别为5.8 mM和0.37 mM。在小鼠中产生类似治疗指数改善的剂量下（2.5 mmol/kg MISO和0.3 mmol/kg BENZO），所达到的血浆和组织浓度将抑制CCNU羟基化30%。对于BENZO而非MISO，在人体可安全达到的浓度下也会发生类似的抑制作用。
