Drug Distribution into Peripheral Nerve

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 of 11 small molecule drugs possessing diverse physicochemical and transport properties and ProTx-II, a tarantula venom peptide with molecular weight of 3826 daltons, in rats. Each drug was administered as constant rate intravenous infusion for 6 h (small molecules) or 24 h (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, brain, spinal cord, sciatic nerve, and DRG. The influence of GF120918, a P-gp and BCRP inhibitor, on peripheral nerve and central nervous system (CNS) tissue penetration of imatinib was also investigated. The results are summarized as follows: 1) the unbound fraction in brain tissue homogenate highly correlates with that in 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 DRG and sciatic nerve; 3) P-gp and BCRP have a limited impact on the distribution of small molecule drugs into peripheral nerve; 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 BNB. Biologics as large as ProTx-II can access DRG but not sciatic nerve and CNS tissues.