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Identification of Metabolites of the Cell-differentiating Agent Hexamethylene Bisacetamide in Humans¹

Department of Medicinal Chemistry/Pharmacognosy, School of Pharmacy, University of Maryland [P. S. C., L. A. G.], and Division of Developmental Therapeutics, University of Maryland Cancer Center [M. J. E., M. S. B. N.], Baltimore, Maryland 21201

Hexamethylene bisacetamide, a compound which in vitro induces differentiation in a wide variety of human and animal cancer cell lines, is being investigated in phase I clinical trials. After i.v. administration of hexamethylene bisacetamide to humans, urine contained the parent compound and at least five metabolites formed by deacetylation and oxidation pathways. Identification of urinary metabolites was accomplished by gas chromatography-mass spectrometric analysis after isolation by ion exchange chromatography or extraction with ethyl acetate. Metabolites with amino or alcohol groups were trifluoroacetylated and acidic functional groups were esterified with 2,2,2-trifluoroethanol or methanol. The structure of each metabolite was confirmed by comparison with authentic standards. Metabolites identified included the major metabolite, 6-acetamidohexanoic acid; the monodeacetylated product, N-acetyl-1,6-diaminohexane; the bis-deacetylated diamine, 1,6-diaminohexane; and the amino acid, 6-aminohexanoic acid and its lactam, caprolactam.

¹ Supported in part by American Cancer Society Institutional Research Grant IN-174D, Maryland Cancer Program/University of Maryland and contract NO1-CM-47734 awarded by the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed.

Received 3/31/86. Revised 6/ 3/86. Accepted 6/23/86.