Translational PKPD Research Group, Department of Pharmaceutical Biosciences, Associate Member of SciLife Lab , Uppsala University , SE-751 24 Uppsala , Sweden.
2-BBB Medicines B.V. , J.H. Oortweg 19 , 2333CH Leiden , The Netherlands.
Mol Pharm. 2018 Dec 3;15(12):5493-5500. doi: 10.1021/acs.molpharmaceut.8b00611. Epub 2018 Nov 8.
Despite the promising features of liposomes as brain drug delivery vehicles, it remains uncertain how they influence the brain uptake in vivo. In order to gain a better fundamental understanding of the interaction between liposomes and the blood-brain barrier (BBB), it is indispensable to test if liposomes affect drugs with different BBB transport properties (active influx or efflux) differently. The aim of this study was to quantitatively evaluate how PEGylated (PEG) liposomes influence brain delivery of diphenhydramine (DPH), a drug with active influx at the BBB, in rats. The brain uptake of DPH after 30 min intravenous infusion of free DPH, PEG liposomal DPH, or free DPH + empty PEG liposomes was compared by determining the unbound DPH concentrations in brain interstitial fluid and plasma with microdialysis. Regular blood samples were taken to measure total DPH concentrations in plasma. Free DPH was actively taken up into the brain time-dependently, with higher uptake at early time points followed by an unbound brain-to-plasma exposure ratio ( K) of 3.0. The encapsulation in PEG liposomes significantly decreased brain uptake of DPH, with a reduction of K to 1.5 ( p < 0.05). When empty PEG liposomes were coadministered with free drug, DPH brain uptake had a tendency to decrease ( K 2.3), and DPH was found to bind to the liposomes. This study showed that PEG liposomes decreased the brain delivery of DPH in a complex manner, contributing to the understanding of the intricate interactions between drug, liposomes, and the BBB.
尽管脂质体作为脑部药物递送载体具有很有前景的特点，但它们如何影响体内的脑部摄取仍然不确定。为了更好地了解脂质体与血脑屏障（BBB）之间的相互作用，有必要测试脂质体是否对具有不同 BBB 转运特性（主动内流或外排）的药物产生不同的影响。本研究的目的是定量评估聚乙二醇（PEG）脂质体如何影响苯海拉明（DPH）在大鼠体内的脑递送，DPH 是一种在 BBB 处具有主动内流的药物。通过微透析法测定脑间质液和血浆中未结合的 DPH 浓度，比较了 30 分钟静脉输注游离 DPH、PEG 脂质体 DPH 或游离 DPH+空 PEG 脂质体后 DPH 的脑摄取情况。定期采集血样，测定血浆中总 DPH 浓度。游离 DPH 时间依赖性地主动摄取到大脑中，早期摄取较高，随后未结合的脑-血浆暴露比（K）为 3.0。PEG 脂质体的包封显著降低了 DPH 的脑摄取，K 值降低至 1.5（p<0.05）。当与游离药物一起给予空 PEG 脂质体时，DPH 的脑摄取有降低的趋势（K 值为 2.3），并且发现 DPH 与脂质体结合。本研究表明，PEG 脂质体以复杂的方式降低了 DPH 的脑递送，有助于理解药物、脂质体和 BBB 之间复杂的相互作用。
