King S Y, Powel R J, Wong Y N, Davidson A F, Vincent D R, Quon C Y, Pieniaszek H J
Drug Metabolism and Pharmacokinetics Section, Du Pont Merck Pharmaceutical Company, Newark, DE 19714.
Res Commun Chem Pathol Pharmacol. 1992 Mar;75(3):259-74.
We studied the influence of chronic moricizine hydrochloride (MRZ) treatment on the drug's pharmacokinetics and on drug metabolizing enzyme activities in rats. Separate groups of 8 rats (4 males and 4 females) were treated with 40 and 100 mg/kg oral MRZ once daily for 7 days and saline control for 7 days prior to the preparation of hepatic microsomal enzyme suspensions. Depending on the substrate, treatments with multiple oral MRZ increased or decreased hepatic microsomal enzyme activities. For the pharmacokinetic study, rats (4 males and 4 females) were treated with 40 mg/kg oral MRZ once daily for 7 days. A comparison of MRZ pharmacokinetics obtained on day 1 relative to day 7 revealed that both AUC0-t and AUC0-infinity increased about 7-fold in males and 2-fold in females. Cmax also increased about 5-fold from day 1 to day 7 in males. These increases in blood concentrations and AUC's are likely due to enzyme inhibition. Results obtained from female rats on days 1, 4 and 7 suggest that metabolic changes probably occur after the 4th day of dosing. Therefore, chronic MRZ treatment affected its pharmacokinetics and hepatic metabolizing enzyme activities in rats.
我们研究了长期给予盐酸莫雷西嗪（MRZ）对大鼠体内该药物药代动力学及药物代谢酶活性的影响。将8只大鼠（4只雄性和4只雌性）分为不同组，分别每日口服40 mg/kg和100 mg/kg的MRZ，持续7天，在制备肝微粒体酶悬浮液前7天给予生理盐水作为对照。根据底物不同，多次口服MRZ治疗可使肝微粒体酶活性升高或降低。在药代动力学研究中，大鼠（4只雄性和4只雌性）每日口服40 mg/kg的MRZ，持续7天。比较第1天和第7天获得的MRZ药代动力学参数发现，AUC0-t和AUC0-∞在雄性大鼠中增加了约7倍，在雌性大鼠中增加了约2倍。Cmax在雄性大鼠中从第1天到第7天也增加了约5倍。血药浓度和AUC的这些增加可能是由于酶抑制作用。雌性大鼠在第1天、第4天和第7天获得的结果表明，代谢变化可能在给药第4天后发生。因此，长期给予MRZ治疗会影响其在大鼠体内的药代动力学及肝脏代谢酶活性。
