白三烯B4受体拮抗剂CP-105,696单次口服给药后在人体的药代动力学和药效学
Pharmacokinetics and pharmacodynamics of the leukotriene B4 receptor antagonist CP-105,696 in man following single oral administration.
作者信息
Liston T E, Conklyn M J, Houser J, Wilner K D, Johnson A, Apseloff G, Whitacre C, Showell H J
机构信息
Department of Drug Metabolism, Pfizer Inc., Groton, CT 06340, USA.
出版信息
Br J Clin Pharmacol. 1998 Feb;45(2):115-21. doi: 10.1046/j.1365-2125.1998.00646.x.
AIMS
CP-105,696, (+)-1-(3S,4R)-[3-(4-phenylbenzyl)-4-hydroxy-chroman-7-yl] cyclopropane carboxylic acid is a potent, novel LTB4 receptor antagonist advanced to clinical trials to determine its efficacy in inflammatory diseases. The pharmacokinetics and pharmacodynamics of CP-105,696 were investigated in healthy male volunteers following oral administration of single doses of 5 to 640 mg.
METHODS
Forty-eight subjects participated in a randomized, double-blind, parallel group study. Plasma and urine concentrations of CP-105,696 were determined at intervals after drug administration. As an indication of LTB4 receptor antagonism following oral administration of CP-105,696, the inhibiton of LTB4-induced upregulation of the neutrophil cell surface complement receptor (CR3), CD11b/CD18, was monitored at 4 h following drug administration using an ex vivo whole blood flow cytometry assay.
RESULTS
Cmax and AUC(0, infinity) increased in a dose-related manner. Respective mean Cmax values were 0.54 to 30.41 microg ml(-1) following doses of 5 to 640 mg. Respective mean AUC(0, infinity) values were 1337 to 16819 microg ml(-1) h for the 40 to 640 mg dose groups. Plasma concentrations declined in a monoexponential manner, with terminal elimination half-lives ranging from 289 to 495 h. Group mean terminal elimination half-lives were dose-independent. Urinary excretion of unchanged drug accounted for < 1% of the administered dose. A linear relationship was observed between CP-105,696 plasma concentrations and inhibition of LTB4-mediated CD11b upregulation on human neutrophils in whole blood. CP-105,696 plasma concentrations of 5-6 microg ml(-1) were necessary to elicit a two-fold shift to the right of the LTB4 concentration response curve for CD11b upregulation.
CONCLUSIONS
These studies demonstrate pharmacologically significant LTB4-receptor antagonism following a single dose of CP-105,696 and pharmacokinetics consistent with once-daily dosing.
目的
CP - 105,696，即(+)-1-(3S,4R)-[3-(4 - 苯基苄基)-4 - 羟基 - 色满 - 7 - 基]环丙烷羧酸，是一种强效的新型白三烯B4（LTB4）受体拮抗剂，已进入临床试验以确定其在炎症性疾病中的疗效。在健康男性志愿者口服单剂量5至640 mg后，对CP - 105,696的药代动力学和药效学进行了研究。
方法
48名受试者参与了一项随机、双盲、平行组研究。给药后每隔一段时间测定CP - 105,696的血浆和尿液浓度。作为口服CP - 105,696后LTB4受体拮抗作用的指标，在给药后4小时使用离体全血流式细胞术测定法监测LTB4诱导的中性粒细胞表面补体受体（CR3）CD11b/CD18上调的抑制情况。
结果
Cmax和AUC(0,∞)呈剂量相关增加。5至640 mg剂量后的各自平均Cmax值为0.54至30.41 μg ml⁻¹。40至640 mg剂量组的各自平均AUC(0,∞)值为1337至16819 μg ml⁻¹·h。血浆浓度以单指数方式下降，终末消除半衰期为289至495小时。组平均终末消除半衰期与剂量无关。原形药物的尿排泄占给药剂量的<1%。在全血中观察到CP - 105,696血浆浓度与LTB4介导的人中性粒细胞CD11b上调抑制之间存在线性关系。CP - 105,696血浆浓度为5 - 6 μg ml⁻¹时，可使CD11b上调的LTB4浓度反应曲线向右移动两倍。
结论
这些研究表明，单次给药CP - 105,696后具有药理学意义的LTB4受体拮抗作用，其药代动力学与每日一次给药一致。
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