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Effects of the aldehyde dehydrogenase inhibitor disulfiram on the plasma pharmacokinetics, metabolism, and toxicity of benzaldehyde dimethane sulfonate (NSC281612, DMS612, BEN) in mice

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Abstract

Purpose

Benzaldehyde dimethane sulfonate (DMS612, NSC281612, BEN) is an alkylator with activity against renal cell carcinoma, currently in phase I trials. In blood, BEN is rapidly metabolized into its highly reactive carboxylic acid (BA), presumably the predominant alkylating species. We hypothesized that BEN is metabolized to BA by aldehyde dehydrogenase (ALDH) and aimed to increase BEN exposure in blood and tissues by inhibiting ALDH with disulfiram, thereby shifting BA production from blood to tissues.

Methods

Female CD2F1 mice were dosed with 20 mg/kg BEN iv alone or 24 h after 300 mg/kg disulfiram ip. BEN, BA, and metabolites were quantitated in plasma and urine, and toxicities were assessed.

Results

BEN had a plasma t½ <5 min and produced at least 12 products. The metabolite half-lives were <136 min. Disulfiram increased BEN plasma exposure 368-fold (AUC0–inf from 0.11 to 40.5 mg/L min), while plasma levels of BA remained similar. Urinary BEN excretion increased (1.0–1.5 % of dose), while BA excretion was unchanged. Hematocrit, white blood cell counts, and percentage lymphocytes decreased after BEN administration. Coadministration of disulfiram appeared to enhance these effects. Profound liver pathology was observed in mice treated with disulfiram and BEN.

Conclusions

BEN plasma concentrations increased after administration of disulfiram, suggesting that ALDH mediates the rapid metabolism of BEN in vivo, which may explain the increased toxicity seen with BEN after administration of disulfiram. Our results suggest that the coadministration of BEN with drugs that inhibit ALDH to patients that are ALDH deficient may cause liver damage.

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Acknowledgments

We thank Diane Mazzei and her colleagues at the University of Pittsburgh Animal Facility for their expert assistance, and the University of Pittsburgh Cancer Institute Hematology/Oncology Writing Group for constructive suggestions regarding the manuscript. Also, we like to thank Dr. Joseph M. Covey at the Toxicology and Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, for his intellectual input. We would like to thank Dr. Merrill Egorin for his help and guidance on conducting the experimentation that was required for this manuscript. He was a great mentor, colleague, and friend, and he will not be forgotten. This work was supported by the National Cancer Institute [Contract N01-CM-52202] and [Grants U01-CA099168, P30-CA47904]. This research was supported in part by the Intramural Research Program of the National Institutes of Health, National Cancer Institute.

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Authors and Affiliations

  1. Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Robert A. Parise & Jan H. Beumer

  2. Molecular Therapeutics/Drug Discovery Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA

    Robert A. Parise, Jan H. Beumer, Dana M. Clausen & Julie L. Eiseman

  3. Melanoma and Skin Cancer Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, 15213, USA

    Jan H. Beumer

  4. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, 15213, USA

    Dana M. Clausen & Julie L. Eiseman

  5. Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, PA, 15261, USA

    Lora H. Rigatti

  6. Division of Hematology and Oncology, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA

    Lora H. Rigatti, Judy A. Ziegler, Maura Gasparetto & Clayton A. Smith

  7. Hillman Research Pavilion, University of Pittsburgh Cancer Center, Room G27E, 5117 Centre Avenue, Pittsburgh, PA, 15213-1863, USA

    Jan H. Beumer

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Correspondence to Jan H. Beumer.

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Parise, R.A., Beumer, J.H., Clausen, D.M. et al. Effects of the aldehyde dehydrogenase inhibitor disulfiram on the plasma pharmacokinetics, metabolism, and toxicity of benzaldehyde dimethane sulfonate (NSC281612, DMS612, BEN) in mice. Cancer Chemother Pharmacol 72, 1195–1204 (2013). https://doi.org/10.1007/s00280-013-2296-5

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  • DOI: https://doi.org/10.1007/s00280-013-2296-5

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