title: Accumulation of BNP7787 in human renal proximal tubule cells.
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 0.6 nmol/10(6) 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.
authors.affiliation: BioNumerik Pharmaceuticals, Inc., San Antonio, Texas 78229, USA. fred.hausheer@bnpi.com
authors.forename: F H
authors.initials: FH
authors.lastname: Hausheer
authors.forename: D
authors.initials: D
authors.lastname: Ding
authors.forename: D
authors.initials: D
authors.lastname: Shanmugarajah
authors.forename: B D
authors.initials: BD
authors.lastname: Leverett
authors.forename: Q
authors.initials: Q
authors.lastname: Huang
authors.forename: X
authors.initials: X
authors.lastname: Chen
authors.forename: H
authors.initials: H
authors.lastname: Kochat
authors.forename: P Y
authors.initials: PY
authors.lastname: Ayala
authors.forename: P N
authors.initials: PN
authors.lastname: Petluru
authors.forename: A R
authors.initials: AR
authors.lastname: Parker
mesh_terms: D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004563:Electrochemistry; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism*; D015080:Mesna / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: C027032:2,2'-dithiodiethanesulfonic acid; D015080:Mesna