Unraveling the role of biological barriers in the development of chemotherapy-induced peripheral neuropathy
Yang Hu 1,2 , Milda Girdenyté 1 , Frida Bällgren 1 , Lieke Roest 1 , Iida Liukkonen 1 , Maria Siskou 1 , Margareta Hammarlund-Udenaes 1 , and Irena Loryan 1 *
1 Translational Pharmacokinetics/Pharmacodynamics Group, Department of Pharmacy, Faculty of Pharmacy, Uppsala University, Box 580, SE-751 23, Uppsala, Sweden
2 Current affiliation: Discovery ADME-Drug discovery sciences, Boehringer Ingelheim RCV GmbH & Co KG, A-1121, Vienna, Austria
* Correspondence to Irena Loryan:
Although drug distribution into the central nervous system (CNS) has been extensively studied, little is known on how drugs are transported into the peripheral nervous system (PNS). It has been shown that blood-tissue barriers in the CNS and PNS differ in their morphological structures, including tight junctions and transporter expression profiles. However, the functional role of PNS barriers on target-site exposure compared to CNS barriers remains poorly understood, requiring systematic neuropharmacokinetic (neuroPK) evaluations. This study aimed to quantitatively assess and compare the extent of drug transport across the blood-brain barrier (BBB), blood-spinal cord barrier (BSCB), blood-nerve barrier (BNB), blood-dorsal root ganglia barrier (BDB), and parenchymal cellular barriers in respective tissues in rats using a set of 11 small molecular weight drugs. Two key neuroPK parameters, namely unbound tissue-to-plasma concentration ratio (K p,uu ) and unbound intracellular-to-extracellular concentration ratio (K p,uu,cell ), were estimated using the Combinatory Mapping Approach. We found that the extent of BDB and BNB transport was significantly greater than that of BBB and BSCB transport, with the difference in K p,uu up to 635-fold observed for vincristine. The extent of drug transport at the BDB was overall the highest. The discrepancy in cellular transport properties was also observed between the investigated PNS and CNS tissues without any universal pattern. This study sheds light on the key features of unbound drug disposition into the dorsal root ganglia and the sciatic nerve vs. brain and spinal cord, providing invaluable insight into the target-site pharmacological/toxicological effects and development of chemotherapy-induced peripheral neuropathy.
This project is funded d by EU IMI2 project NeuroDeRisk, grant# 821528.