Irreversible binding of an anticancer compound (BI-94) to plasma proteins. (October 2015)

• Record Type: Journal Article
• Authors: Gautam, Nagsen; Thakare, Rhishikesh; Rana, Sandeep; Natarajan, Amarnath; Alnouti, Yazen
• Is Part Of: Xenobiotica. Volume 45:Number 10(2015:Oct.)
• Page Start: 858
• Page End: 873
• Publication Date: 2015-10
• Subjects: Metabolism -- Periodicals; Drugs -- Physiological effect -- Periodicals; Food additives -- Periodicals; Chemicals -- Physiological effect -- Periodicals; Biochemistry -- Periodicals; Pharmaceutical Preparations -- metabolism -- Periodicals; Metabolism -- Periodicals; 574.133
• Languages: English
• ISSNs: 0049-8254

Abstract

<abstract> <title>Abstract</title> <p>1. We investigated the mechanisms responsible for the <italic>in vivo</italic> instability of a benzofurazan compound BI-94 (NSC228148) with potent anti-cancer activity.</p> <p>2. BI-94 was stable in MeOH, water, and in various buffers at pHs 2.5–5, regardless of the buffer composition. In contrast, BI-94 was unstable in NaOH and at pHs 7–9, regardless of the buffer composition. BI-94 disappeared immediately after spiking into mice, rat, monkey, and human plasma. BI-94 stability in plasma can be only partially restored by acidifying it, which indicated other mechanisms in addition to pH for BI-94 instability in plasma.</p> <p>3. BI-94 formed adducts with the trapping agents, glutathione (GSH) and <italic>N</italic>-acetylcysteine (NAC), <italic>in vivo</italic> and <italic>in vitro</italic> via nucleophilic aromatic substitution reaction. The kinetics of adduct formation showed that neutral or physiological pHs enhanced and accelerated GSH and NAC adduct formation with BI-94, whereas acidic pHs prevented it. Therefore, physiological pHs not only altered BI-94 chemical stability but also enhanced adduct formation with endogenous nucleophiles. In addition, adduct formation with human serum albumin-peptide 3 (HSA-T3) at the Cys34 position was demonstrated.</p> <p>4. In conclusion, BI-94 was unstable at physiological conditions due to chemical instability and irreversible binding to plasma proteins.</p> </abstract>