METHODS: Ondansetron (10 mg/kg) and tariquidar (7.5 mg/kg) were administered intravenously, plasma and tissue samples were collected and analyzed by HPLC. A mathematical model with brain, spinal cord, cerebrospinal fluid and two systemic disposition compartments was developed to describe the data.
RESULTS: The results demonstrate that tariquidar at 7.5 mg/kg resulted in a complete inhibition of Pgp efflux of ondansetron in the brain and spinal cord. The compartmental model successfully captured pharmacokinetics of ondansetron in wild type and Pgp knockout (KO) animals receiving the drug alone or in wild type animals receiving the ondansetron and tariquidar combination.
CONCLUSIONS: The study provided important quantitative information on enhancement of CNS exposure to ondansetron using co-administration of Pgp Inhibitor in a rat model, which will be further utilized in conducting a clinical study. Tariquidar co-administration resulted in ondansetron CNS exposure comparable to observed in Pgp KO rats. Results also highlighted the effect of tariquidar on plasma disposition of ondansetron, which may not be dependent on Pgp inhibition, and should be evaluated in future studies.
方法:昂丹司琼(10mg/kg)和塔基达(7.5mg/kg)静脉注射,收集血浆和组织样品并通过HPLC分析。一个有大脑的数学模型,脊髓,开发了脑脊液和两个全身处置区室来描述数据。
结果:结果表明,7.5mg/kg的Tariquidar完全抑制了大脑和脊髓中昂丹司琼的Pgp外排。隔室模型成功地捕获了单独接受药物的野生型和Pgp敲除(KO)动物或接受昂丹司琼和塔基达组合的野生型动物中的昂丹司琼的药代动力学。
结论:该研究提供了在大鼠模型中使用Pgp抑制剂联合给药增强中枢神经系统暴露于昂丹司琼的重要定量信息,这将进一步用于进行临床研究。Tariquidar共同给药导致昂丹司琼CNS暴露与PgpKO大鼠中观察到的相当。结果还强调了塔基达对昂丹司琼血浆处置的影响,这可能不依赖于Pgp抑制,并应在未来的研究中进行评估。