Wong S L, Drajesk J, Chang M, Lanni C, Witt G, Hansen R, Awni W M
Department of Pharmacokinetics and Biopharmaceutics, Abbott Laboratories, Abbott Park, IL 60064-3500, USA.
Clin Pharmacol Ther. 1998 Mar;63(3):324-31. doi: 10.1016/S0009-9236(98)90164-3.
This study evaluated the safety, pharmacokinetics and pharmacodynamics of ABT-761 [R(+)-N-[3-[5-(4-fluorophenylmethyl)-2-thienyl]-1- methyl-2-propynyl]-N-hydroxyurea], a new N-hydroxyurea analog.
This was a randomized, double-blind, placebo-controlled, single- and multiple-dose (15-day) study of ABT-761 (50 to 200 mg/day) in healthy, nonsmoking adult male volunteers. The pharmacokinetics were evaluated by investigation of the time- and dose-dependent effects of ABT-761, and the pharmacologic selectivity of ABT-761 was evaluated based on calcium ionophore-stimulated leukotriene B4 (LTB4) and thromboxane B2 (TXB2) biosynthesis ex vivo in whole blood.
After single and multiple doses, mean observed time to reach maximum concentration values of ABT-761 ranged from 4.0 to 7.5 hours. Mean values for maximum concentration and area under the plasma concentration-time curve from 0 to 24 hours increased approximately linearly with dose. Mean terminal half-life and apparent volume of distribution during the terminal elimination phase of ABT-761 ranged from 15.4 to 17.8 hours and 69.5 to 78.9 L, respectively, and was dose independent. Steady state was reached on day 11 after multiple dosing. Less than 0.05% of unchanged ABT-761 was recovered in urine within the 24-hour period after day 15 dosing. Population ABT-761 plasma concentration at which 50% of the maximum possible inhibition was observed for LTB4 inhibition was 0.24 microgram/ml. No differences in mean TXB2 inhibition were observed between the subjects receiving ABT-761 and placebo.
These results indicate that ABT-761 is a potent and selective inhibitor of 5-lipoxygenase and the pharmacokinetics of ABT-761 are time and dose independent between 50 and 200 mg/day after single and multiple dosing.
本研究评估了新型N - 羟基脲类似物ABT - 761[R(+)-N-[3-[5-(4 - 氟苯基甲基)-2 - 噻吩基]-1 - 甲基 - 2 - 丙炔基]-N - 羟基脲]的安全性、药代动力学和药效学。
这是一项针对健康、不吸烟成年男性志愿者的随机、双盲、安慰剂对照、单剂量和多剂量（15天）研究，研究药物为ABT - 761（50至200毫克/天）。通过研究ABT - 761的时间和剂量依赖性效应评估药代动力学，并基于钙离子载体刺激全血中白三烯B4（LTB4）和血栓素B2（TXB2）的体外生物合成评估ABT - 761的药理选择性。
单剂量和多剂量给药后，ABT - 761达到最大浓度值的平均观察时间为4.0至7.5小时。最大浓度和0至24小时血浆浓度 - 时间曲线下面积的平均值随剂量大致呈线性增加。ABT - 761终末消除相的平均终末半衰期和表观分布容积分别为15.4至17.8小时和69.5至78.9升，且与剂量无关。多次给药后第11天达到稳态。第15天给药后24小时内，尿液中未变化的ABT - 761回收率低于0.
