Syvänen Stina, Xie Rujia, Sahin Selma, Hammarlund-Udenaes Margareta
Division of Pharmacokinetics and Drug Therapy, Department of Pharmaceutical Biosciences, Uppsala University, Box 591, 751 24, Uppsala, Sweden.
Pharm Res. 2006 Apr;23(4):705-17. doi: 10.1007/s11095-006-9780-0. Epub 2006 Apr 7.
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.
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.
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(p,uu).
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(p,uu), but does influence the total brain-to-blood ratio K(p) and the time to reach steady state in the brain.
本模拟研究的目的是探讨与通透性相关的外排过程的性质、位置和能力如何影响脑内药物浓度。
脑内药物浓度降低可能是由于摄取受阻，即存在于管腔膜上的一种“守门人”功能，这一功能已被认为与ABCB1（P-糖蛋白）有关，或者是由于转运体增强了外排作用，这些转运体在管腔膜或基底外侧膜的一侧摄取分子，并在另一侧释放它们。使用计算机程序MATLAB建立了包括被动转运、摄取受阻和外排增强的药代动力学模型。模拟基于吗啡、吗啡-3-葡萄糖醛酸苷、吗啡-6-葡萄糖醛酸苷和加巴喷丁的实验参数。
摄取受阻过程在降低脑内药物浓度方面更为有效。外排增强会缩短药物在脑内的半衰期，而摄取受阻时半衰期与被动转运时相似。药物在血脑屏障上的摄取和外排之间的关系决定了未结合药物在脑与血浆中的稳态浓度比K(p,uu)。
低通透性和高通透性药物均可达到相同的稳态浓度比，尽管达到稳态的时间会有所不同。脑内未结合药物的分布容积不影响K(p,uu)，但会影响总脑血比K(p)以及脑内达到稳态的时间。
