Matsuno Hiroyuki, Uematsu Toshihiko, Niwa Masayuki, Kozawa Osamu, Nagashima Satoru, Kohno Ken-Ichi, Kato Hiroki, Kawabata Yoshihiro, Yoshida Yasuhisa, Kanamaru Mitsutaka
Department of Pharmacology, Gifu University School of Medicine, Japan.
J Clin Pharmacol. 2002 Jul;42(7):782-90. doi: 10.1177/009127002401102722.
The pharmacokinetics and pharmacodynamics of a new oral thromboxane (TX) A2 receptor antagonist, Z-335, were studied in healthy male volunteers following single doses (0.5-40 mg, PO) in a dose-escalating manner and multiple doses (40 mg, PO, once daily for 7 consecutive days) with a single-blind, placebo-controlled design. Serial blood and urine samples were analyzed for Z-335 and its metabolites to obtain key pharmacokinetic parameters. In the single-dose (10, 20, and 40 mg) study, the maximum plasma concentration (Cmax) and area under the plasma concentration versus time curve (AUC) increased in proportion to the dose when administered afterfasting, while the mean elimination half-life (t1/2beta) was essentially unchanged (7.79-7.93 h). Recovery of the unchanged and taurine-conjugated drugs in the urine within 24 hours was 6.5% to 8.4% and 11.9% to 14.2%, respectively. These parameters essentially remained unchanged when the effect of meal intake was evaluated at the dose of 20 mg with a crossover design. Ex vivo platelet aggregation in the plasma by a TXA2 analogue, U46619, was completely inhibited within 2 hours after all doses, and complete inhibition was maintained for 12 to 14 hours, depending on the dose. The aggregation induced by collagen was also inhibited to a lesser extent, whereas that by adenosine diphosphate was hardly influenced. In the multiple-dose study, Cmax and AUC0-24 were increased by 34% after the last dose compared with the first dose. Z-335 afforded extensive inhibition of platelet aggregation by U46619 throughout the administration period, which returned, however, almost to the control level 48 hours after the last dose. The agent was well tolerated without any abnormalities in subjective and objective symptoms, blood biochemistry, hematology, and urinalysis definitely attributable to the agent, except for the changes expected from its TXA2 receptor-antagonizing actions. Z-335 was concluded to be safe and to provide long-lasting blockade of TXA2 receptors on the basis of a once-daily regimen, promoting further clinical evaluation.
采用单盲、安慰剂对照设计，以剂量递增方式对健康男性志愿者单次给予新型口服血栓素（TX）A2受体拮抗剂Z - 335（0.5 - 40 mg，口服），并多次给予（40 mg，口服，连续7天，每日1次），研究其药代动力学和药效学。对系列血液和尿液样本进行Z - 335及其代谢物分析，以获得关键药代动力学参数。在单剂量（10、20和40 mg）研究中，空腹给药后，最大血浆浓度（Cmax）和血浆浓度-时间曲线下面积（AUC）与剂量成比例增加，而平均消除半衰期（t1/2β）基本不变（7.79 - 7.93小时）。24小时内尿液中未变化药物和牛磺酸结合药物的回收率分别为6.5%至8.4%和11.9%至14.2%。采用交叉设计在20 mg剂量评估进餐影响时，这些参数基本保持不变。所有剂量给药后2小时内，TXA2类似物U46619诱导的离体血浆血小板聚集被完全抑制，并根据剂量不同，完全抑制状态维持12至14小时。胶原蛋白诱导的聚集也受到较小程度抑制，而二磷酸腺苷诱导的聚集几乎未受影响。在多剂量研究中，末次给药后Cmax和AUC0 - 24较首次给药时增加了34%。在整个给药期间，Z - 335对U46619诱导的血小板聚集有广泛抑制作用，但在末次给药后48小时几乎恢复到对照水平。除了其TXA2受体拮抗作用所预期的变化外，该药物耐受性良好，主观和客观症状、血液生化、血液学及尿液分析均无明确归因于该药物的异常。基于每日一次给药方案，得出Z - 335安全且能对TXA2受体产生持久阻断作用的结论，促进了进一步的临床评估。
