QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.105.008516v1 34/6/984    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tevell, A. Articles by Hedeland, M. Search for Related Content PubMed PubMed Citation Articles by Tevell, A. Articles by Hedeland, M.

FLUTAMIDE METABOLISM IN FOUR DIFFERENT SPECIES IN VITRO AND IDENTIFICATION OF FLUTAMIDE METABOLITES IN HUMAN PATIENT URINE BY HIGH PERFORMANCE LIQUID CHROMATOGRAPHY/TANDEM MASS SPECTROMETRY

Department of Medicinal Chemistry, Division of Analytical Pharmaceutical Chemistry (A.T., U.B.), Department of Pharmacy (H.L., M.J.), and Department of Pharmaceutical Biosciences, Division of Biochemistry (M.N.), Uppsala University, Uppsala, Sweden; Department of Oncology, Sahlgrenska Academy, Göteborg University, Göteborg, Sweden (B.L); and Department of Chemistry, National Veterinary Institute, Uppsala, Sweden (M.H., U.B.)

A new metabolic scheme of flutamide is proposed in this article. Some patients treated with flutamide, a nonsteroidal antiandrogen, have developed severe hepatic dysfunction. Toxic metabolites have been proposed to be responsible for these negative effects. In this study, the qualitative aspects of the in vitro metabolism of flutamide in liver microsomes from human, dog, pig, and rat were evaluated. A direct comparison of the flutamide metabolism in liver and prostate microsomes from pig was made, and the in vivo metabolism of flutamide was investigated in urine from orally treated prostate cancer patients. Liquid chromatography/tandem mass spectrometry was used for analysis. The mass spectrometer was equipped with an electrospray interface and operated in the negative ion mode. In liver microsomes from pig, dog, and rat, extensive hydroxylation of flutamide occurred. One, two, or three hydroxy groups were attached, and isomeric forms were detected for both monohydroxylated and trihydroxylated drug. In pig liver microsomes, isomers of a third metabolite, hydroxylated 4-nitro-3-(trifluoromethyl)-aniline, were also found after incubation with either flutamide or 2-hydroxyflutamide. In human liver microsomes, the pharmacologically active 2-hydroxyflutamide was the only metabolite detected. Several phase I metabolites as well as four intact phase II metabolites could be recovered from the urine samples. For the first time in humans, glucuronic acid conjugates of hydroxylated 4-nitro-3-(trifluoromethyl)-aniline, and mono- and dihydroxylated flutamide were identified, together with hydroxylated 4-nitro-3-(trifluoromethyl)-aniline conjugated with sulfate. In addition, one mercapturic acid conjugate of hydroxylated flutamide, probably formed from flutamide via a reactive intermediate, was detected.

This article has been cited by other articles:

				P. Kang, D. Dalvie, E. Smith, S. Zhou, A. Deese, and J. A. Nieman Bioactivation of Flutamide Metabolites by Human Liver Microsomes Drug Metab. Dispos., July 1, 2008; 36(7): 1425 - 1437. [Abstract] [Full Text] [PDF]

				P. Kang, D. Dalvie, E. Smith, S. Zhou, and A. Deese Identification of a Novel Glutathione Conjugate of Flutamide in Incubations with Human Liver Microsomes Drug Metab. Dispos., July 1, 2007; 35(7): 1081 - 1088. [Abstract] [Full Text] [PDF]