Drug Distribution into Peripheral Nerve

Abstract

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 -[4-[2-(6,7-dimethoxy-3,4-dihydro-1-isoquinolin-2-yl)ethyl]phenyl]-5-methoxy-9-oxo-10-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.

The NaV1.7 Channel Subtype as an Antinociceptive Target for Spider Toxins in Adult Dorsal Root Ganglia Neurons

“…Dorsal root ganglia present a rich capillary bed in cell body area ( Figure 2 ), with the particularity of high fenestrations between two endothelial cells being permeable to low and high molecular weight compounds ( Petterson and Olsson, 1989 ; Parke and Whalen, 2002 ; Jimenez-Andrade et al, 2008 ; Berta et al, 2017 ). In contrast to the cell body area, the nerve fiber area wrapped by the epineural sheath, i.e., the dura mater continuum in peripheral nervous system (PNS), presents a blood-nerve barrier similar to the CNS blood-brain barrier (BNB), with a lot of tight junctions between cells that prevent the passage of unwanted drugs ( Jimenez-Andrade et al, 2008 ; Liu et al, 2018 ).…”

“…ProTx-II and its mutant, despite being the best candidate toxins with the highest affinity and selectivity, are unable to pass through the BNB (see Figure 2 ) and inhibit action potential transmission along nerves, except if a disruption of the perineurial barrier occurs ( Schmalhofer et al, 2008 ; Hackel et al, 2012 ). After 24 h of intravenous infusion in vivo , ProTx-II can access DRG neurons but not sciatic nerves and CNS tissues ( Liu et al, 2018 ). Thus, the fenestrations in Blood-Glangia-Barrier (BGB, see Figure 2 ) are the entry doors for large peptide toxins but their spreading to dorsal root of spinal cord and to distal nerve endings will depend on BNB.…”

P‐Glycoprotein Inhibition Exacerbates Paclitaxel Neurotoxicity in Neurons and Patients With Cancer

“…Thus, Mdr1a(−/−) mice had increased accumulation of vinblastine in the sciatic nerve, 38 whereas recent studies did not support a role of P-gp in drug distribution to the peripheral nervous system in Mdr1a(−/−) rats. 39,40 Whether these discordant data are caused by species differences or other factors is unknown.…”

Trigeminal neuropathic pain development and maintenance in rats are suppressed by a positive modulator of α6 GABAA receptors

“…However, the pharmacological targets of DK‐I‐56‐1 may also be located more rostrally, such as in the synaptic terminals of α6‐containing TG neurons in the spinal trigeminal subnucleus caudalis, or anywhere else in the trigeminal pain pathway, and thus behind the blood–brain barrier (Shibuta et al, ). Independently of where the α6‐containing receptors are located that mediate the effects of DK‐I‐56‐1, its pharmacologically effective concentration is expected to be related to the brain concentration; namely, it has recently been demonstrated that the unbound fraction in brain tissue homogenates of a set of several low molecular weight drugs highly correlates with that in the dorsal root ganglion, which can be taken as a more general surrogate for the situation in peripheral nerve tissue (Liu et al, ).…”