Equilibrative Nucleoside Transporter Mediated Drug Disposition Across the Blood-Testis Barrier

Abstract

The blood-testis barrier (BTB) protects developing germ cells by limiting entry of toxicants. This protective barrier poses a problem for therapeutic disposition to the male genital tract, which may allow viruses or cancer to persist in the testis, and impedes the development of male contraceptives and fertility treatments. Drug transporters present at the basal and apical membranes of testicular epithelial cells (Sertoli cells) facilitate the disposition of therapeutics across the BTB. Many antivirals and chemotherapeutic agents are classified as nucleoside analogs, which resemble endogenous nucleosides essential for nucleic acid synthesis and spermatogenesis. Due to similarity in chemical structure, these drugs are suspected to be substrates of the equilibrative nucleoside transporters (ENTs). The ENTs create a transepithelial transport pathway consisting of ENT1 at the basal membrane of Sertoli cells and ENT2 at the apical membrane of Sertoli cells. Therefore, nucleoside analog drugs that are substrates of ENT1 and ENT2 can circumvent the BTB for therapeutic benefit. The purpose of these studies was to investigate ENT1 and ENT2- mediated transport, use the resulting data to build computational models that can predict drug interactions with ENT1 and ENT2 and validate these predictions with in vivo studies. The results of these studies are foundational to identifying additional drugs that can cross the BTB through the ENT1-ENT2 transepithelial transport pathway, which has implications for improving and informing the drug discovery and development process for antivirals, chemotherapeutics, male contraceptives and fertility treatments.