Pharmacokinetic consequences of active drug efflux at the blood-brain barrier
Pharmacokinetic consequences of active drug efflux at the blood-brain barrier
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DOI：
10.1007/s11095-006-9780-0
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发表时间：
2006-04-01
影响因子：
3.7
通讯作者：
Hammarlund-Udenaes, M
中科院分区：
文献类型：
--
作者：
Syvänen, S;Xie, RJ;Hammarlund-Udenaes, M
目的.本模拟研究的目的是调查如何的性质，位置和能力的外排过程中的渗透性能影响脑浓度。脑浓度降低可能是由于流入障碍。管腔膜中的看门人功能，已被认为是ABCB 1（P-糖蛋白），或通过转运蛋白（在管腔或近管腔膜的一侧拾取分子并在另一侧释放它们）的流出增强。使用计算机程序MATLAB建立包括被动转运、内流阻碍和外排增强的药代动力学模型。模拟基于实验获得的吗啡、吗啡-3-葡糖苷酸、吗啡-6-葡糖苷酸和加巴喷丁的参数。流入阻碍过程对于保持脑浓度较低更有效。外排增强降低了药物在脑中的半衰期，而内流阻碍的半衰期与被动转运相似。药物穿过血脑屏障的流入和流出之间的关系决定了未结合药物K-puu的脑与血浆浓度的稳态比。渗透性差和渗透性高的药物都可以达到相同的稳态比，尽管达到稳态的时间不同。未结合药物在脑中的分布容积不影响K-puu，但确实影响总脑血比K-p和脑中达到稳态的时间。
Purpose. The objective of this simulation study was to investigate how the nature, location, and capacity of the efflux processes in relation to the permeability properties influence brain concentrations.Methods. Reduced brain concentrations can be due to either influx hindrance. a gatekeeper function in the luminal membrane, which has been suggested for ABCB1 (P-glycoprotein), or efflux enhancement by transporters that pick up molecules on one side of the luminal or abluminal membrane and release them on the other side. Pharmacokinetic models including passive transport, influx hindrance, and efflux enhancement were built using the computer program MATLAB. The simulations were based on experimentally obtained parameters for morphine, morphine-3-glucuronide, morphine-6-glucuronide, and gabapentin.Results. The influx hindrance process is the more effective for keeping brain concentrations low. Efflux enhancement decreases the half-life of the drug in the brain, whereas with influx hindrance the half-life is similar to that seen with passive transport. The relationship between the influx and efflux of the drug across the blood-brain barrier determines the steady-state ratio of brain to plasma concentrations of unbound drug, K-puu.Conclusions. Both poorly and highly permeable drugs can reach the same steady-state ratio, although the time to reach steady state will differ. The volume of distribution of unbound drug in the brain does not influence K-puu, but does influence the total brain-to-blood ratio K-p, and the time to reach steady state in the brain.