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Exemestane (EXE) is an aromatase inhibitor used for the prevention and treatment of estrogen receptor-positive breast cancer. Although the known major metabolic pathway for EXE is reduction to form the active 17 β -dihydro-EXE (17 β -DHE) and subsequent glucuronidation to 17 β -hydroxy-EXE-17-O- β -D-glucuronide (17 β -DHE-Gluc), previous studies have suggested that other major metabolites exist for exemestane. In the present study, a liquid chromatography-mass spectrometry (LC-MS) approach was used to acquire accurate mass data in MS E mode, in which precursor ion and fragment ion data were obtained simultaneously to screen novel phase II EXE metabolites in urine specimens from women taking EXE. Two major metabolites predicted to be cysteine conjugates of EXE and 17 β -DHE by elemental composition were identified. The structures of the two metabolites were confirmed to be 6-methylcysteinylandrosta-1,4-diene-3,17-dione (6-EXE-cys) and 6-methylcysteinylandrosta-1,4-diene-17 β -hydroxy-3-one (6-17 β -DHE-cys) after comparison with their chemically synthesized counterparts. Both underwent biosynthesis in vitro in three stepwise enzymatic reactions, with the first involving glutathione conjugation. The cysteine conjugates of EXE and 17 β -DHE were subsequently quantified by liquid chromatography-mass spectrometry in the urine and matched plasma samples of 132 subjects taking EXE. The combined 6-EXE-cys plus 6-17 β -DHE-cys made up 77% of total EXE metabolites in urine (vs. 1.7%, 0.14%, and 21% for EXE, 17 β -DHE, and 17 β -DHE-Gluc, respectively) and 35% in plasma (vs. 17%, 12%, and 36% for EXE, 17 β -DHE, and 17 β -DHE-Gluc, respectively). Therefore, cysteine conjugates of EXE and 17 β -DHE appear to be major metabolites of EXE in both urine and plasma., (Copyright © 2018 The Author(s).)

The purpose of this study was to investigate the metabolism and disposition of fluticasone furoate, an enhanced-affinity glucocorticoid receptor agonist, in humans. In a two-part, open-label design study, five healthy male subjects received a p.o. dose of 2 mg of [(14)C]fluticasone furoate, followed 4 weeks later by an i.v. dose of 0.25 mg of [(14)C]fluticasone furoate (as a 30-min infusion). Oral absorption was rapid and estimated at approximately 30%, although the oral bioavailability was markedly lower at 1.6%, limited by extensive first-pass metabolism. Plasma clearance was 58.3 l/h, with a volume of distribution of 642 liters and a terminal elimination half-life of 15.3 h. The major circulating component identified in plasma extracts after i.v. and p.o. dosing was unchanged parent compound, with 17beta-carboxylic acid (GW694301X; M10) also being notable after p.o. administration. Mean recovery of radioactivity was approximately 92 and 102% at 216 and 168 h after i.v. and p.o. administration, respectively, with most (at least 90%) recovered in the feces. Fluticasone furoate was extensively metabolized, with only trace amounts of unchanged parent compound observed in feces following either route of administration. The predominant pathway was removal of the S-fluoromethyl carbothioate group to yield GW694301X (M10). Other pathways included oxidative defluorination to yield a hydroxyl at the C6 position. There was no evidence for metabolic loss of the furoate group from fluticasone furoate or any of its metabolites. Evidence presented suggests that enterocytes have a role in the metabolism of unabsorbed fluticasone furoate.