Effects of the aldehyde dehydrogenase inhibitor disulfiram on the plasma pharmacokinetics, metabolism, and toxicity of benzaldehyde dimethane sulfonate (NSC281612, DMS612, BEN) in mice.
OBJECTIVE
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.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
Robert A
RA
Parise
Jan H
JH
Beumer
Dana M
DM
Clausen
Lora H
LH
Rigatti
Judy A
JA
Ziegler
Maura
M
Gasparetto
Clayton A
CA
Smith
Julie L
JL
Eiseman
D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000633:toxicity; D019540:Area Under Curve; D001547:Benzaldehydes / Q000493:pharmacokinetics* / Q000633:toxicity; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000473:pathology; D004221:Disulfiram / Q000494:pharmacology*; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006207:Half-Life; D051379:Mice
D000970:Antineoplastic Agents; D001547:Benzaldehydes; D004791:Enzyme Inhibitors; C492379:NSC281612; D000444:Aldehyde Dehydrogenase; D004221:Disulfiram