The testis and epididymis mark the initial portion of the male genital tract (MGT) and are impermeable to most hydrophilic compounds due to tight junctions. This barrier ? the blood- testes barrier (BTB) ? can act as an obstacle for therapies requiring entry into these tissues for full effect; for example contributing to testicular relapse in acute lymphoblastic leukemia (ALL) or acting as a sanctuary site for HIV infection. However, these epithelial barriers are known to express alternative xenobiotic transporters that may be utilized to allow select agents to gain access to the MGT and reduce the frequency of testicular relapse or HIV transmission. Rather than studying why drugs fail to cross the BTB, the major focus of our studies is to characterize the endogenous transport processes that could allow drugs to access the MGT. We hypothesize that the penetration of MGT relevant drugs into the BTB occurs through transport processes that can be modeled computationally, and that therapeutic concentration of these drugs is greatly affected by epididymal transporters and water reabsorption. Our grant focuses on 3 aims:
Aim 1 : Establish the transepithelial transport mechanisms by which MGT relevant drugs can cross the BTB and develop a predictive model for rational therapeutic design.
Aim 2 : Determine the impact of epididymal water reabsorption on drug concentrations within the MGT in vivo.
Aim 3 : Determine whether nucleoside transport is supported in the epididymis and the impact on nucleoside-based drug disposition. Understanding these pathways will be foundational for the development of drugs, such as antiviral, chemotherapy, contraception, and fertility agents, that require access to the MGT in order to achieve full therapeutic effect.

Public Health Relevance

The blood-testis barrier keeps drugs from reaching the male genital tract which may contribute to problems such as testicular relapse in acute lymphoblastic leukemia (ALL) or acting as a sanctuary site for HIV infection. This project seeks to determine the molecular mechanisms whereby specific nucleoside analog drugs can cross the blood-testis barrier and to evaluate the possibility of utilizing endogenous transporter systems as a means of circumventing the blood-testis barrier. This mechanism could be utilized in the development of new drug therapies such as chemotherapy, antiviral, contraception, and fertility agents that require access to the MGT in order to achieve full therapeutic effect.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM123643-03
Application #
9606499
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Okita, Richard T
Project Start
2017-04-01
Project End
2020-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Arizona
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Toth, Erica L; Li, Hui; Dzierlenga, Anika L et al. (2018) Gene-by-Environment Interaction of Bcrp-/- and Methionine- and Choline-Deficient Diet-Induced Nonalcoholic Steatohepatitis Alters SN-38 Disposition. Drug Metab Dispos 46:1478-1486
Dzierlenga, Anika L; Cherrington, Nathan J (2018) Misregulation of membrane trafficking processes in human nonalcoholic steatohepatitis. J Biochem Mol Toxicol 32:e22035
Miller, Siennah R; Cherrington, Nathan J (2018) Transepithelial transport across the blood–testis barrier Reproduction :