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

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.

• Authors: Robert A Parise, Jan H Beumer, Dana M Clausen, Lora H Rigatti, Judy A Ziegler, Maura Gasparetto, Clayton A Smith, Julie L Eiseman
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 72 Issue 6 Pg. 1195-204 (Dec 2013) ISSN: 1432-0843 [Electronic] Germany
• PMID: 24061865 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural)

Chemical References

• Antineoplastic Agents
• Benzaldehydes
• Enzyme Inhibitors
• NSC281612
• Aldehyde Dehydrogenase
• Disulfiram

Topics

• Aldehyde Dehydrogenase (antagonists & inhibitors)
• Animals
• Antineoplastic Agents (pharmacokinetics, toxicity)
• Area Under Curve
• Benzaldehydes (pharmacokinetics, toxicity)
• Chemical and Drug Induced Liver Injury (etiology, pathology)
• Disulfiram (pharmacology)
• Drug Interactions
• Enzyme Inhibitors (pharmacology)
• Female
• Half-Life
• Mice