Larrey D, Tinel M, Pessayre D
Biochem Pharmacol. 1983 May 1;32(9):1487-93. doi: 10.1016/0006-2952(83)90470-7.
The effects of some macrolides (4 mmoles . kg-1 p.o. daily for 4 days in vivo; 0.3 mM in vitro) on hepatic drug-metabolizing enzymes in rats were compared. One group of macrolides including previously studied compounds (oleandomycin, erythromycin and troleandomycin), as well as several other erythromycin derivatives, showed induction of microsomal enzymes and formation of inactive cytochrome P-450-metabolite complexes in vivo; this formation increased in the order: oleandomycin, erythromycin ethylsuccinate, erythromycin stearate, erythromycin itself, erythromycin propionate, erythromycin estolate and troleandomycin. Troleandomycin and, to a lesser extent, erythromycin and oleandomycin formed cytochrome P-450-metabolite complexes when incubated in vitro with 1 mM NADPH and microsomes from rats pretreated with troleandomycin or phenobarbital, but not with microsomes from control rats or rats treated with 3-methylcholanthrene. In contrast, two other macrolides, josamycin and midecamycin, showed no induction of microsomal enzymes and no detectable formation of cytochrome P-450-metabolite complexes in vivo. In vitro, these macrolides failed to form detectable complexes even with microsomes from rats pretreated with troleandomycin or phenobarbital. Hexobarbital sleeping time was unaffected by preadministration of josamycin or midecamycin (4 mmoles . kg-1 p.o.) 2 hr earlier; the in vitro activity of hexobarbital hydroxylase was not inhibited by 0.3 mM josamycin or midecamycin. We conclude that, unlike several erythromycin derivatives, josamycin and midecamycin do not form inactive cytochrome P-450-metabolite complexes in rats.
比较了一些大环内酯类药物（体内每日口服4 mmol·kg⁻¹，共4天；体外0.3 mM）对大鼠肝脏药物代谢酶的影响。一组大环内酯类药物包括先前研究过的化合物（竹桃霉素、红霉素和醋竹桃霉素）以及其他几种红霉素衍生物，在体内显示出微粒体酶的诱导作用以及无活性细胞色素P - 450 - 代谢物复合物的形成；这种形成按以下顺序增加：竹桃霉素、琥乙红霉素、硬脂酸红霉素、红霉素本身、丙酸红霉素、依托红霉素和醋竹桃霉素。醋竹桃霉素以及在较小程度上的红霉素和竹桃霉素，在体外与1 mM烟酰胺腺嘌呤二核苷酸磷酸（NADPH）以及用醋竹桃霉素或苯巴比妥预处理的大鼠微粒体一起孵育时会形成细胞色素P - 450 - 代谢物复合物，但与对照大鼠或用3 - 甲基胆蒽处理的大鼠的微粒体一起孵育时则不会。相比之下，另外两种大环内酯类药物，交沙霉素和麦迪霉素，在体内未显示出微粒体酶的诱导作用，也未检测到细胞色素P - 450 - 代谢物复合物的形成。在体外，即使与用醋竹桃霉素或苯巴比妥预处理的大鼠微粒体一起孵育，这些大环内酯类药物也未能形成可检测到的复合物。提前2小时口服交沙霉素或麦迪霉素（4 mmol·kg⁻¹）对己巴比妥睡眠时间没有影响；0.3 mM交沙霉素或麦迪霉素对己巴比妥羟化酶的体外活性没有抑制作用。我们得出结论，与几种红霉素衍生物不同，交沙霉素和麦迪霉素在大鼠体内不会形成无活性的细胞色素P - 450 - 代谢物复合物。
