Central nervous system concentrations of cyclooxygenase-2 inhibitors in humans
Central nervous system concentrations of cyclooxygenase-2 inhibitors in humans
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DOI：
10.1097/00000542-200502000-00026
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发表时间：
2005-02-01
期刊：
影响因子：
8.8
通讯作者：
Kharasch, ED
中科院分区：
文献类型：
--
作者：
Dembo, G;Park, SB;Kharasch, ED
背景：环氧合酶-2 (COX-2) - 选择性抑制剂 (coxib) 正在研究其潜在的治疗、减弱或预防神经炎症和神经退行性疾病的作用。考昔布也是疼痛治疗的重大进步，传统上被认为通过外周作用实现镇痛。然而，在动物中，中枢神经系统 (CNS) COX-2 活性和前列腺素类浓度因外周炎症而增加，中枢敏化已被认为可以解释长期疼痛相关现象，并且考昔布可达到显着的脑脊液 (CSF) 浓度，并可能通过 CNS 作用引起镇痛。然而，目前尚不清楚是否或哪些考昔布到达人类的中枢神经系统。这项研究根据脑脊液浓度确定了考昔布是否可以到达人体中枢神经系统。方法：十名健康人类志愿者同时接受单剂量口服塞来考昔 (200 毫克)、罗非考昔 (50 毫克) 和伐地考昔 (40 毫克)。对血液和脑脊液连续取样 10 小时，并通过质谱法对血浆总和未结合的昔布浓度以及脑脊液昔布浓度进行定量。结果：三种昔布的血浆总浓度和达到最大血浆浓度的时间相似。相反，未结合的（游离）血浆浓度差异显着。塞来考昔、罗非考昔和伐地考昔的最大未结合血浆浓度分别为 1.4 +/- 0.5、42 +/- 17 和 6.0 +/- 2.9 ng/ml。 COX-2抑制剂迅速渗透中枢神经系统。塞来考昔、罗非考昔和伐地考昔的最大 CSF 浓度分别为 2 +/- 2、57 +/- 25 和 10 4 ng/ml。罗非考昔和伐地考昔的 CSF 浓度超过了 COX-2 的中位抑制浓度，但塞来考昔则不然。结论：这些结果表明，考昔布确实到达人体中的 CNS，且渗透速度快，且浓度明显足以抑制 COX-2 活性。昔布之间的脑脊液渗透率存在显着差异。未结合（游离）血浆昔布浓度是脑脊液浓度的主要决定因素。这支持了这样的假设：考昔布可能部分地作用于人类中枢神经系统，提供有关疼痛机制和治疗的重要新信息，并且当需要中枢神经系统渗透时可以指导治疗试验中考昔布的选择。
Background: Cyclooxygenase-2 (COX-2)--selective inhibitors (coxibs) are under investigation for the potential therapy, attenuation, or prevention of neuroinflammatory and neurodegenerative disorders. Coxibs are also a significant advance in pain therapy and are traditionally considered to achieve analgesia via peripheral effects. However, in animals, central nervous system (CNS) COX-2 activity and prostanoid concentrations are increased by peripheral inflammation, central sensitization has been proposed to account for long-term pain-related phenomena, and coxibs achieve significant cerebrospinal fluid (CSF) concentrations and may cause analgesia via CNS action. Nevertheless, it remains unknown whether or which coxibs reach the CNS in humans. This investigation determined whether coxibs can reach the CNS in humans, based on CSF concentrations.Methods: Ten healthy human volunteers simultaneously received a single oral dose of celecoxib (200 mg), rofecoxib (50 mg), and valdecoxib (40 mg). Blood and CSF were serially sampled for 10 h, and plasma total and unbound and CSF coxib concentrations were quantified by mass spectrometry.Results: Total plasma concentrations and time to maximum plasma concentration were similar among the three coxibs. In contrast, unbound (free) plasma concentrations differed significantly. Maximum unbound plasma concentrations were 1.4 +/- 0.5, 42 +/- 17, and 6.0 +/- 2.9 ng/ml, respectively, for celecoxib, rofecoxib, and valdecoxib. COX-2 inhibitors rapidly penetrated the CNS. Maximum CSF concentrations were 2 +/- 2, 57 +/- 25, and 10 4 ng/ml, respectively, for celecoxib, rofecoxib, and valdecoxib. CSF concentrations exceeding the median inhibitory concentration for COX-2 were achieved by rofecoxib and valdecoxib but not celecoxib.Conclusions: These results show that coxibs do reach the CNS in humans, with rapid penetration, and in concentrations apparently sufficient to inhibit COX-2 activity. There were significant differences among coxibs in CSF penetration. Unbound (free) plasma coxib concentration was the major determinant of CSF concentration. This supports the hypothesis that coxibs may act, in part, in the human CNS, provide important new information on the mechanism and treatment of pain and may guide coxib selection for therapeutic trials when CNS penetration is desirable.