METABOLISM OF AMINOGLUTETHIMIDE IN HUMANS - IDENTIFICATION OF 4 NEW URINARY METABOLITES

  • 1 January 1984
    • journal article
    • research article
    • Vol. 12  (4) , 511-516
Abstract
Four new metabolites of aminoglutethimide [used to treat hormone-dependent breast cancer in postmenopausal women] were identified in the urine of patients being treated chronically with the drug. These were products of hydroxylation of the 3-ethylpiperidine-2,6-dione residue, i.e., 3-(4-aminophenyl)-3-ethyl-5-hydroxypiperidine-2,6-dione and its acetylamino analog, 3-(4-aminophenyl)-3-(1-hydroxyethyl)piperidine-2,6-dione, and 3-(4-aminophenyl)-3-(2-carboxamidoethyl)tetrahydrofuran-2-one, the lactone formed by rearrangement of 3-(4-aminophenyl)-3-(2-hydroxyethyl)piperidine-2,6-dione. The metabolites were isolated by reverse-phase TLC and characterized by comparison of their mass spectra either with those of synthetic samples or with the mass spectra of analogous metabolites previously identified in the urine of rats. These new metabolites were minor constituents compared with aminoglutethimide and with the previously identified major metabolites 3-(4-acetylaminophenyl)-3-ethylpiperidine-2,6-dione and 3-(4-hydroxylaminophenyl)-3-ethylpiperidine-2,6-dione. There were marked species differences between rat and human inasmuch as almost all the metabolites in the urine of the rat were N-acetylated whereas most of the human metabolites were not. 5-Hydroxylation of the piperidinedione residue was stereoselective in the same sense in both species, the cis isomer being formed exclusively. Synthetic cis-3-(4-aminophenyl)-3-ethyl-5-hydroxypiperidine-2,6-dione did not inhibit the activity of the target enzyme systems desmolase and aromatase in vitro and, therefore, like other metabolites so far described, is an inactivation product of the drug.