Fukazawa H, Iwase H, Ichishita H, Takizawa T, Shimizu H
Drug Metab Dispos. 1975 Jul-Aug;3(4):235-44.
After oral administration of bromazepam, 50 mg/kg/day for 14-28 days to rats, the rate of elimination of the unchanged drug from the blood increased by 20-40%, as determined from the half-lives of the blood decay curves during the first 4 hr after administration of an oral or intravenous test dose of bromazepam. During the chronic administration, the liver weight increased 30-40%, with concomitant enlargement of the liver. The hepatomegaly was associated with elevation of microsomal drug-metabolizing enzyme activities, including that responsible for the oxidation of bromazepam itself. Spectral characteristics of the isolated microsomes indicated that the manner by which bromazepam caused the elevation (induction) of the enzyme activities was of the "phenobarbital type" rather than the "methylcholanthrene type." Since certain steps of bromazepam metabolism take place in the liver, it appears reasonable to assume that the increase in the elimination rate found after chronic administration may depend upon the enhanced drug-metabolizing activities in the liver. The hepatomegaly and the associated elevation of enzyme activities returned to the normal states within 7 days after withdrawal of the drug. Neither the increase in the elimination rate nor the enzyme induction was observed with doses lower than 5 mg/kg.
给大鼠口服溴西泮，剂量为50毫克/千克/天，持续14 - 28天，根据口服或静脉注射测试剂量的溴西泮后最初4小时内血液衰变曲线的半衰期测定，血液中未变化药物的消除率提高了20 - 40%。在长期给药期间，肝脏重量增加了30 - 40%，同时肝脏肿大。肝肿大与微粒体药物代谢酶活性升高有关，包括负责溴西泮自身氧化的酶。分离出的微粒体的光谱特征表明，溴西泮引起酶活性升高（诱导）的方式是“苯巴比妥类型”而非“甲基胆蒽类型”。由于溴西泮代谢的某些步骤在肝脏中发生，所以可以合理推测长期给药后发现的消除率增加可能取决于肝脏中药物代谢活性的增强。停药后7天内，肝肿大及相关酶活性升高恢复到正常状态。低于5毫克/千克的剂量未观察到消除率增加或酶诱导现象。
