Accumulation of BNP7787 in human renal proximal tubule cells

F. H. Hausheer, D. Ding, D. Shanmugarajah, B. D. Leverett, Q. Huang, X. Chen, H. Kochat, P. Y. Ayala, P. N. Petluru, A. R. Parker

Research output: Contribution to journalArticle

Abstract

BNP7787, an investigational drug undergoing global Phase III development, appears to have potential advantages over other cytoprotective compounds that have been evaluated for preventing and mitigating cisplatin-induced nephrotoxicity. Herein, we characterized the in vitro accumulation of BNP7787 in human renal proximal tubule cells (HK-2) in which cisplatin is known to be taken up and accumulate. HK-2 cells were incubated with pharmacological concentrations of BNP7787 for varying times. Temperature-dependent accumulation of BNP7787 in cells was observed and the BNP7787-derived metabolite, mesna, formed intracellularly was directly monitored. The peak level of BNP7787-derived mesna measured in HK-2 cells was approximately 0.6nmol/106 cells; this is pharmacologically similar to reported platinum concentrations in kidney cells and may be sufficient to afford nephroprotection. Therefore, in addition to previously suggested glomerular filtration, the cellular accumulation of BNP7787 by HK-2 cells is a plausible newly identified mechanism by which BNP7787 may accumulate in renal tubular cells, where it can exert its pharmacological effects to protect against cisplatin-induced nephrotoxicity by direct covalent conjugation of mesna with cisplatin, or by the formation of BNP7787-derived mesna-disulfide heteroconjugates that exert nephroprotective effects by inhibition of the key toxification enzyme targets γ-glutamyltranspeptidase and aminopeptidase N.

Original languageEnglish (US)
Pages (from-to)3977-3984
Number of pages8
JournalJournal of Pharmaceutical Sciences
Volume100
Issue number9
DOIs
StatePublished - Sep 2011
Externally publishedYes

Keywords

  • Active Transport
  • BNP7787
  • Cancer
  • Chemoprotectant
  • Cisplatin nephrotoxicity
  • HPLC
  • Mensa
  • Nephroprotection
  • Pharmacodynamics
  • Rental transport

ASJC Scopus subject areas

  • Pharmaceutical Science

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  • Cite this

    Hausheer, F. H., Ding, D., Shanmugarajah, D., Leverett, B. D., Huang, Q., Chen, X., Kochat, H., Ayala, P. Y., Petluru, P. N., & Parker, A. R. (2011). Accumulation of BNP7787 in human renal proximal tubule cells. Journal of Pharmaceutical Sciences, 100(9), 3977-3984. https://doi.org/10.1002/jps.22510