Plasma and cerebrospinal fluid pharmacokinetics of ondansetron in humans.
Plasma and cerebrospinal fluid pharmacokinetics of ondansetron in humans.
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DOI：
10.1111/bcp.14412
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发表时间：
2021-03
影响因子：
3.4
通讯作者：
Haroutounian S
中科院分区：
文献类型：
--
作者：
Chiang MD;Frey K;Lee C;Kharasch ED;Tallchief D;Sawyer C;Blood J;Back H;Kagan L;Haroutounian S
与CNS中5-HT 3受体过表达相关的多巴胺能感觉调节的变化与外周神经损伤后神经病理性疼痛的病理生理学有关。5-HT 3受体拮抗剂如昂丹司琼可以潜在地减轻神经性疼痛，但由于潜在地受限的CNS通路而具有有限的有效性。然而，目前有关全身给药5-HT 3受体拮抗剂的中枢神经系统分布的信息有限。本研究评价了昂丹司琼的脑脊液（CSF）处置，作为CNS渗透的替代品。15例患者接受单次16 mg昂丹司琼静脉输注15 min，随后进行系列血液和单次CSF采样。采用群体PK建模方法描述昂丹司琼的平均和个体血浆和CSF特征。使用双房室模型捕获昂丹司琼血浆PK，单CSF房室模型描述CNS分布。个体模型估计的CSF-昂丹司琼血浆分配系数在0.09和0.20之间。这些值反映在计算的CSF渗透率中，范围为0.08至0.26。静脉给药后，昂丹司琼的CSF浓度比血浆中观察到的浓度低约7倍。基于单个CSF数据点，可以开发模型来描述昂丹司琼的个体CSF浓度-时间曲线。昂丹司琼的低CSF渗透性可以解释其有限的镇痛效果，并提供了一个机会，探索提高其CNS渗透性的目标条件，如神经性疼痛。
Changes in serotonergic sensory modulation associated with overexpression of 5-HT3 receptors in the CNS have been implicated in the pathophysiology of neuropathic pain after peripheral nerve damage. 5-HT3 receptor antagonists such as ondansetron can potentially alleviate neuropathic pain, but have limited effectiveness, due potentially to limited CNS access. However, there is currently limited information on CNS disposition of systemically-administered 5-HT3 receptor antagonists. This study evaluated the cerebrospinal fluid (CSF) disposition of ondansetron, as a surrogate of CNS penetration. Fifteen patients were given a single 16 mg intravenous 15 min infusion of ondansetron, followed by serial blood and a single CSF sampling. Population PK modeling approach was implemented to describe the average and individual plasma and CSF profiles of ondansetron. A two-compartmental model was used to capture ondansetron plasma PK with a single CSF compartment to describe distribution to the CNS. The individual model-estimated CSF to plasma partition coefficients of ondansetron were between 0.09 and 0.20. These values were mirrored in the calculated CSF penetration ratios, ranging from 0.08 to 0.26. After intravenous administration, CSF concentrations of ondansetron were approximately 7-fold lower than those observed in the plasma. A model could be developed to describe individual CSF concentration time profiles of ondansetron based on a single CSF data point. The low CSF penetration of ondansetron may explain its limited analgesic effectiveness, and affords an opportunity to explore enhancing its CNS penetration for targeting conditions such as neuropathic pain.
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影响因子：
2.8
作者：
Tzvetkov, M. V.;Saadatmand, A. R.;Brockmoeller, J.
通讯作者：
Brockmoeller, J.
影响因子：
2.5
作者：
de Lange, Elizabeth C. M.
通讯作者：
de Lange, Elizabeth C. M.
影响因子：
2.9
作者：
CHITOUR, D;DICKENSON, AH;LEBARS, D
通讯作者：
LEBARS, D
DOI：
10.1016/s0378-4347(97)00068-6
发表时间：
1997-06-06
期刊：
JOURNAL OF CHROMATOGRAPHY B
影响因子：
--
作者：
Depot, M;Leroux, S;Caille, G
通讯作者：
Caille, G
影响因子：
7.4
作者：
Suzuki, R;Rahman, W;Dickenson, AH
通讯作者：
Dickenson, AH