mp8b00611_si_001.pdf (680.88 kB)
In Vivo Quantitative Understanding of PEGylated Liposome’s Influence on Brain Delivery of Diphenhydramine
journal contribution
posted on 2018-10-30, 00:00 authored by Yang Hu, Pieter J. Gaillard, Jaap Rip, Elizabeth C.M. de Lange, Margareta Hammarlund-UdenaesDespite
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 (Kp,uu) of 3.0. The encapsulation
in PEG liposomes significantly decreased brain uptake of DPH, with
a reduction of Kp,uu to 1.5 (p < 0.05). When empty PEG liposomes were coadministered with free
drug, DPH brain uptake had a tendency to decrease (Kp,uu 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.