Feuer G
Drug Metab Rev. 1983;14(6):1119-44. doi: 10.3109/03602538308991424.
In this review evidence is provided for the interaction between various drugs and steroid hormones in man and between drugs and progestogens in experimental animals. The mechanism by which these drug interactions occur are of fundamental biochemical and pharmacological interest. The importance of practical clinical considerations of drug-steroid interactions has also been discussed. In particular, considering the present tendency to lower the dose of progestogen and estrogen in most contraceptive preparations, any factor that reduces the bioavailability of the steroid hormones becomes very important. Other drugs and environmental chemicals may interact with these steroids and thereby diminish their efficacy. Clinical studies have reported that the most important interfering drugs are some anticonvulsants and antibiotics, and the antituberculosis compound rifampicin. Anticonvulsants and antituberculotics affect microsomal enzyme induction in the liver or interfere with enzyme systems in the gut wall. The action of antibiotics is connected with the pharmacokinetics of contraceptive steroids by an interaction with their enterohepatic circulation. Some environmental factors such as smoking, alcohol, and other dietary variations, and concurrent hepatic disease may modify the disposition of circulating endogenous steroids and exogenous contraceptive steroids. These effects may alter their response accordingly. In our studies drug treatments of rats reduced serum progesterone level irrespective of whether a potent inducer (phenobarbital, 4-methylcoumarin) or a hepatotoxin (carbon tetrachloride, coumarin, alpha-naphthylisothiocyanate) was administered. These treatments affected hepatic progesterone content. Phenobarbital and carbon tetrachloride reduced serum level, but the hepatic incorporation was enhanced by phenobarbital and reduced by carbon tetrachloride. The opposite actions were selective; phenobarbital raised the oxidative pathway of progesterone metabolism but did not modify the reductive pathway. This drug also enhanced progesterone 16 alpha-, 6 beta-, and 20 alpha-hydroxylase, but did not alter delta 4 - 5 alpha-reductase. In contrast, carbon tetrachloride inhibited hydroxylase and enhanced reductase activities. The effects of these test compounds on progesterone-metabolizing enzymes in isolated microsomes in vitro were similar to the in vivo results. It is concluded that the action of various drugs on serum and liver progesterone levels and metabolism is probably related to changes manifest in the function of the hepatic endoplasmic reticulum.
本综述提供了关于人类中各种药物与甾体激素之间以及实验动物中药物与孕激素之间相互作用的证据。这些药物相互作用发生的机制具有基本的生化和药理学意义。还讨论了药物 - 甾体相互作用在实际临床考虑中的重要性。特别是，考虑到目前大多数避孕制剂中降低孕激素和雌激素剂量的趋势，任何降低甾体激素生物利用度的因素都变得非常重要。其他药物和环境化学物质可能与这些甾体相互作用，从而降低它们的功效。临床研究报告称，最重要的干扰药物是一些抗惊厥药、抗生素以及抗结核化合物利福平。抗惊厥药和抗结核药会影响肝脏中的微粒体酶诱导作用或干扰肠壁中的酶系统。抗生素的作用通过与甾体避孕药的肠肝循环相互作用而与甾体避孕药的药代动力学相关。一些环境因素，如吸烟、饮酒、其他饮食变化以及并发的肝脏疾病，可能会改变循环中内源性甾体和外源性避孕甾体的处置。这些影响可能会相应地改变它们的反应。在我们的研究中，对大鼠进行药物治疗会降低血清孕酮水平，无论给予的是强效诱导剂（苯巴比妥、4 - 甲基香豆素）还是肝毒素（四氯化碳、香豆素、α - 萘基异硫氰酸酯）。这些治疗会影响肝脏中的孕酮含量。苯巴比妥和四氯化碳会降低血清水平，但苯巴比妥会增强肝脏摄取，而四氯化碳会降低肝脏摄取。相反的作用具有选择性；苯巴比妥提高了孕酮代谢的氧化途径，但未改变还原途径。这种药物还增强了孕酮16α -、6β - 和20α - 羟化酶，但未改变Δ4 - 5α - 还原酶。相比之下，四氯化碳抑制羟化酶并增强还原酶活性。这些受试化合物对体外分离微粒体中孕酮代谢酶的影响与体内结果相似。结论是，各种药物对血清和肝脏孕酮水平及代谢的作用可能与肝内质网功能的变化有关。
