Enhancement of zidovudine transfer to molt-4 cells, a human t-cell model, by dehydroepiandrosterone sulfate

Tomohiro Nishimura, Jun Tanaka, Masatoshi Tomi, Yoshiaki Seki, Noriko Kose, Yoshimichi Sai, Emi Nakashima

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

A possible approach to improve antiretroviral therapy with nucleoside reverse transcriptase inhibitors is to enhance inhibitor delivery to CD4-positive T cells. We previously showed that dehydroepiandrosterone sulfate (DHEAS) enhances zidovudine (AZT) transfer into syncytiotrophoblast. Here, we investigated whether DHEAS also enhances AZT transfer into a cellular model of human T lymphocytes, and whether AZT is taken up by a specific transport system. The effects of DHEAS and related compounds on the uptake of [3H]AZT and other nucleosides by Molt-4 cells (a model of human CD4-positive T cells) were measured. [3H]AZT uptake by Molt-4 cells was nitrobenzylthioinosine insensitive and pH dependent, and the uptake was significantly inhibited by 1 mM ethylisopropylamiloride. [3H]AZT uptake by Molt-4 cells was increased in the presence of DHEAS, whereas uptake of other nucleosides was reduced. Kinetic study revealed that the maximum uptake velocity (up to 30 min) was increased in the presence of DHEAS. The structural requirements for AZT uptake-enhancing activity were studied using structural analogues of DHEAS. Estrone-3-sulfate and 16α-hydroxy DHEAS also enhanced AZT uptake into Molt-4 cells. The use of uptake enhancers may be a good strategy to improve the efficacy of antiretroviral therapy.

Original languageEnglish
Pages (from-to)3959-3967
Number of pages9
JournalJournal of Pharmaceutical Sciences
Volume100
Issue number9
DOIs
Publication statusPublished - 2011 Sep

Keywords

  • AZT
  • Antiretroviral drug
  • Distribution
  • Drug interactions
  • Drug targeting
  • Permeation enhancers
  • Transporter

ASJC Scopus subject areas

  • Pharmaceutical Science

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