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

This Article Full Text Full Text (PDF) All Versions of this Article: dmd.107.014860v1 35/7/1081    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 Kang, P. Articles by Deese, A. Search for Related Content PubMed PubMed Citation Articles by Kang, P. Articles by Deese, A.

Identification of a Novel Glutathione Conjugate of Flutamide in Incubations with Human Liver Microsomes

Pharmacokinetics Dynamics and Metabolism (P.K., D.D., E.S., S.Z.) and Analytical Research and Development (A.D.), Pfizer Global Research and Development, San Diego, California

Flutamide, a nonsteroidal antiandrogen drug widely used in the treatment of prostate cancer, has been associated with rare incidences of hepatotoxicity in patients. It is believed that bioactivation of flutamide and subsequent covalent binding to cellular proteins is responsible for its toxicity. Current in vitro studies were undertaken to probe the cytochrome P450 (P450)-mediated bioactivation of flutamide and identify the possible reactive species using reduced glutathione (GSH) as a trapping agent. NADPH- and GSH-supplemented human liver microsomal incubations of flutamide gave rise to a novel GSH conjugate where GSH moiety was conjugated to the flutamide molecule via the amide nitrogen, resulting in a sulfenamide. The structure of the conjugate was characterized by liquid chromatography-tandem mass spectrometry and NMR experiments. The conjugate formation was primarily catalyzed by heterologously expressed CYP2C19, CYP1A2, and, to a lesser extent, CYP3A4 and CYP3A5. The mechanism for the formation of this conjugate is unknown; however, a tentative bioactivation mechanism involving a P450-catalyzed abstraction of hydrogen atom from the amide nitrogen of flutamide and the subsequent trapping of the nitrogen-centered radical by GSH or oxidized glutathione (GSSG) was proposed. Interestingly, the same adduct was formed when flutamide was incubated with human liver microsomes in the presence of GSSG and NADPH. This finding suggests that P450-mediated oxidation of flutamide via a nitrogen-centered free radical could be one of the several bioactivation pathways of flutamide. Even though the relationship of the GSH conjugate to flutamide-induced toxicity is unknown, the results have revealed the formation of a novel, hitherto unknown, GSH adduct of flutamide.

This article has been cited by other articles:

				M. Ohbuchi, M. Miyata, D. Nagai, M. Shimada, K. Yoshinari, and Y. Yamazoe Role of Enzymatic N-Hydroxylation and Reduction in Flutamide Metabolite-Induced Liver Toxicity Drug Metab. Dispos., January 1, 2009; 37(1): 97 - 105. [Abstract] [Full Text] [PDF]

				H. Takakusa, H. Masumoto, H. Yukinaga, C. Makino, S. Nakayama, O. Okazaki, and K. Sudo Covalent Binding and Tissue Distribution/Retention Assessment of Drugs Associated with Idiosyncratic Drug Toxicity Drug Metab. Dispos., September 1, 2008; 36(9): 1770 - 1779. [Abstract] [Full Text] [PDF]

				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]