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Pharmacokinetic Modeling of the Impact of P-glycoprotein on Ondansetron Disposition in the Central Nervous System
Pharmaceutical Research ( IF 3.5 ) Pub Date : 2020-09-28 , DOI: 10.1007/s11095-020-02929-2
Manting Chiang 1, 2 , Hyun-Moon Back 1, 2 , Jong Bong Lee 1 , Sarah Oh 1 , Tiffany Guo 1 , Simone Girgis 1 , Celine Park 1 , Simon Haroutounian 3 , Leonid Kagan 1, 2
Affiliation  

Purpose

Modulation of 5-HT3 receptor in the central nervous system (CNS) is a promising approach for treatment of neuropathic pain. The goal was to evaluate the role of P-glycoprotein (Pgp) in limiting exposure of different parts of the CNS to ondansetron (5-HT3 receptor antagonist) using wild-type and genetic knockout rat model.

Methods

Plasma pharmacokinetics and CNS (brain, spinal cord, and cerebrospinal fluid) disposition was studied after single 10 mg/kg intravenous dose.

Results

Pgp knockout resulted in significantly higher concentrations of ondansetron in all tested regions of the CNS at most of the time points. The mean ratio of the concentrations between KO and WT animals was 2.39–5.48, depending on the region of the CNS. Male and female animals demonstrated some difference in ondansetron plasma pharmacokinetics and CNS disposition. Mechanistic pharmacokinetic model that included two systemic disposition and three CNS compartments (with intercompartmental exchange) was developed. Pgp transport was incorporated as an efflux from the brain and spinal cord to the central compartment. The model provided good simultaneous description of all data sets, and all parameters were estimated with sufficient precision.

Conclusions

The study provides important quantitative information on the role of Pgp in limiting ondansetron exposure in various regions of the CNS using data from wild-type and Pgp knockout rats. CSF drug concentrations, as a surrogate to CNS exposure, are likely to underestimate the effect of Pgp on drug penetration to the brain and the spinal cord.



中文翻译:

P-糖蛋白对中枢神经系统昂丹司琼分布影响的药代动力学模型

目的

调节中枢神经系统 (CNS) 中的 5-HT3 受体是治疗神经性疼痛的有前景的方法。目的是使用野生型和基因敲除大鼠模型评估 P-糖蛋白 (Pgp) 在限制 CNS 不同部分暴露于昂丹司琼(5-HT3 受体拮抗剂)中的作用。

方法

在单次 10 mg/kg 静脉给药后研究血浆药代动力学和 CNS(脑、脊髓和脑脊液)分布。

结果

在大多数时间点,Pgp 敲除导致中枢神经系统所有测试区域中昂丹司琼浓度显着升高。KO 和 WT 动物之间的平均浓度比为 2.39-5.48,取决于 CNS 的区域。雄性和雌性动物在昂丹司琼血浆药代动力学和中枢神经系统分布方面表现出一些差异。开发了包括两个全身处置和三个 CNS 隔室(具有隔室交换)的机制药代动力学模型。Pgp 运输被纳入作为从大脑和脊髓到中央隔室的流出物。该模型提供了对所有数据集的良好同时描述,并且所有参数的估计都具有足够的精度。

结论

该研究使用来自野生型和 Pgp 敲除大鼠的数据,提供了关于 Pgp 在限制中枢神经系统不同区域的昂丹司琼暴露中的作用的重要定量信息。作为 CNS 暴露的替代指标,CSF 药物浓度可能低估了 Pgp 对药物渗透到大脑和脊髓的影响。

更新日期:2020-09-28
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