PT  - JOURNAL ARTICLE
AU  - Houfu Liu
AU  - Yan Chen
AU  - Liang Huang
AU  - Xueying Sun
AU  - Tingting Fu
AU  - Shengqian Wu
AU  - Xiaoyan Zhu
AU  - Wei Zhen
AU  - Jihong Liu
AU  - Gang Lu
AU  - Wei Cai
AU  - Ting Yang
AU  - Wandong Zhang
AU  - Xiaohong Yu
AU  - Zehong Wan
AU  - Jianfei Wang
AU  - Scott G. Summerfield
AU  - Kelly Dong
AU  - Georg C. Terstappen
TI  - Drug Distribution into Peripheral Nerve
AID  - 10.1124/jpet.117.245613
DP  - 2018 May 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 336--345
VI  - 365
IP  - 2
4099  - http://jpet.aspetjournals.org/content/365/2/336.short
4100  - http://jpet.aspetjournals.org/content/365/2/336.full
SO  - J Pharmacol Exp Ther2018 May 01; 365
AB  - Little is known about the impact of the blood–nerve barrier (BNB) on drug distribution into peripheral nerves. In this study, we examined the peripheral nerve penetration in rats of 11 small-molecule drugs possessing diverse physicochemical and transport properties and ProTx-II, a tarantula venom peptide with molecular mass of 3826 Daltons. Each drug was administered as constant rate intravenous infusion for 6 hours (small molecules) or 24 hours (ProTx-II). Blood and tissues including brain, spinal cord, sciatic nerve, and dorsal root ganglion (DRG) were collected for drug concentration measurements. Unbound fractions of a set of compounds were determined by equilibrium dialysis method in rat blood, brains, spinal cords, sciatic nerves, and DRG. We also investigated the influence of N-[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxo-10H-acridine-4-carboxamide (GF120918), a P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) inhibitor, on the peripheral nerve and central nervous system (CNS) tissue penetration of imatinib. We found that: 1) the unbound fraction in brain tissue homogenate highly correlates with that in the spinal cord, sciatic nerve, and DRG for a set of compounds and thus provides a good surrogate for spinal cord and peripheral nerve tissues, 2) small-molecule drugs investigated can penetrate the DRG and sciatic nerve, 3) P-gp and BCRP have a limited impact on the distribution of small-molecule drugs into peripheral nerves, and 4) DRG is permeable to ProTx-II, but its distribution into sciatic nerve and CNS tissues is restricted. These results demonstrate that small-molecule drugs investigated can penetrate peripheral nerve tissues, and P-gp/BCRP may not be a limiting factor at the BNB. Biologics as large as ProTx-II can access the DRG but not sciatic nerve and CNS tissues.