Abstract 5465: Modulation of DMS612 (BEN) pharmacokinetics and metabolism in mice by disulfiram, and aldehyde dehydrogenase inhibitor

Abstract

Abstract Introduction: DMS612 (NSC 281612, BEN) is an alkylating agent in clinical trials based on its in vitro and in vivo activity against renal cell carcinoma. We previously reported that BEN is rapidly metabolized into its carboxylic acid (BA), and that BEN and BA undergo chemical degradation both in vitro and in vivo. In addition, we demonstrated that BEN is rapidly metabolized into at least 13 different analytes in vivo. We hypothesized that BEN is metabolized to BA by aldehyde dehydrogenase (ALDH). In an attempt to increase the exposure to BEN, we explored the effect of the ALDH inhibitor disulfiram on the pharmacokinetics of BEN in mice. Materials & Methods: Female CD2F1 mice were dosed with either 20 mg/kg BEN i.v. alone or 24 h after the i.p. administration of 300 mg/kg disulfiram. Plasma and urine concentrations of BEN and its metabolites were quantitated by LC-MS/MS. Plasma pharmacokinetic parameters were calculated non-compartmentally. Urinary excretion of BEN and metabolites was calculated as percentage of the dose. Results: BEN was metabolized to at least 13 different products as previously reported. In the BEN alone study, BEN was metabolized quickly with a half-life <5 min. The half-lives of the metabolites were < 2 h. Pretreatment with disulfiram resulted in a 300-fold increase in exposure to BEN, from AUC0-inf 143 ng/mL*min to 40,515 ng/mL*min, while BA exposure remained similar, at AUC0-inf 254,280 ng/mL*min after BEN alone to AUC0-inf 274,947 ng/mL*min after disulfiram. In addition, the half-lives and AUCs of some of the metabolites in the BEN + disulfiram study appeared to be longer than when BEN was administered alone. Urinary excretion of BEN was increased 50% after disulfiram (from 1% to 1.5 % of the dose), BA excretion accounted for 5.8% of the dose after BEN alone and this was not markedly affected by disulfiram pretreatment. Conclusions: BEN is rapidly metabolized into many metabolites, which could affect the efficacy of BEN as an anti-neoplastic agent. We have demonstrated that by administering the ALDH inhibitor disulfiram the exposure to BEN is greatly increased, suggesting that ALDH is at least partly responsible for the rapid metabolism of BEN. However, the plasma exposure to BA increased only 8%. Our results will aid in the interpretation of ongoing clinical studies with BEN, which include genotyping for ALDH. Support: N01-CM07106, N01-CM52202, P30-CA47904. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5465. doi:10.1158/1538-7445.AM2011-5465