Wong S L, O'Dea R F, Dube L M, Awni W M
Abbott Laboratories, Abbott Park, Illinois 60064-3500, USA.
J Clin Pharmacol. 1998 Jul;38(7):642-8. doi: 10.1002/j.1552-4604.1998.tb04472.x.
ABT-761 is a second-generation 5-lipoxygenase inhibitor in clinical development for the treatment of asthma. The effects of ABT-761 on the pharmacokinetics of an oral contraceptive were assessed in 21 female adult volunteers in a phase I, multiple-dose, open-label study. Subjects received a single dose of oral contraceptive (30 microg ethinyl estradiol and 0.15 mg of levonorgestrel) on each of days 1 and 29. Oral doses of 300 mg of ABT-761 were administered once daily beginning on day 15 continuing through day 29. Statistically significant decreases in maximum concentration (Cmax) and area under the concentration-time curve (AUC) of ethinyl estradiol were observed when oral contraceptive was administered concomitantly with ABT-761 compared with administration of oral contraceptive alone. The mean elimination rate constant of ethinyl estradiol increased by 30% (a mean decrease of 3.8 hours in half-life), and the mean apparent volume of distribution during the terminal phase (Vd(beta)/F) of ethinyl estradiol increased by 73% in the presence of ABT-761. Mean Cmax and AUC values for norgestrel decreased by 12% and 10%, respectively, when administered with ABT-761. Mean values for time to Cmax (tmax), terminal rate constant (beta), half-life (t1/2), and Vd(beta)/F of norgestrel were similar when oral contraceptive was administered alone or concomitantly with ABT-761. The mechanism responsible for the effect of ABT-761 on the clearance of ethinyl estradiol remains undefined. Because results of previous multiple-dose studies of ABT-761 do not provide any evidence of autoinduction, the effects of ABT-761 on the pharmacokinetics of ethinyl estradiol are more likely related to absorption of ethinyl estradiol.
ABT - 761是一种正在进行临床开发用于治疗哮喘的第二代5 - 脂氧合酶抑制剂。在一项I期、多剂量、开放标签研究中，对21名成年女性志愿者评估了ABT - 761对口服避孕药药代动力学的影响。受试者在第1天和第29天各接受一剂口服避孕药（30微克炔雌醇和0.15毫克左炔诺孕酮）。从第15天开始至第29天，每天口服一次300毫克ABT - 761。与单独服用口服避孕药相比，当口服避孕药与ABT - 761同时服用时，观察到炔雌醇的最大浓度（Cmax）和浓度 - 时间曲线下面积（AUC）有统计学意义的下降。在ABT - 761存在的情况下，炔雌醇的平均消除速率常数增加了30%（半衰期平均缩短3.8小时），炔雌醇终末相的平均表观分布容积（Vd(beta)/F）增加了73%。与ABT - 761一起服用时，炔诺孕酮的平均Cmax和AUC值分别下降了12%和10%。单独服用口服避孕药或与ABT - 761同时服用时，炔诺孕酮的达峰时间（tmax）、终末速率常数（beta）、半衰期（t1/2）和Vd(beta)/F的平均值相似。ABT - 761影响炔雌醇清除率的机制尚不清楚。由于之前ABT - 761多剂量研究的结果未提供任何自身诱导的证据，ABT - 761对炔雌醇药代动力学的影响更可能与炔雌醇的吸收有关。
