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Flutamide metabolis...
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
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- Tevell, Annica (author)
- Uppsala universitet,Institutionen för läkemedelskemi,Analytisk Farmaceutisk kemi
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- Lennernäs, Hans (author)
- Uppsala universitet,Institutionen för farmaci
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Jonsson, M. (author)
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- Norlin, Maria (author)
- Uppsala universitet,Institutionen för farmaceutisk biovetenskap,Farm biokemi
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- Lennernäs, Bo, 1963 (author)
- Gothenburg University,Göteborgs universitet,Institutionen för kliniska vetenskaper,Institute of Clinical Sciences
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- Bondesson, Ulf (author)
- Uppsala universitet,Institutionen för läkemedelskemi,Analytisk Farmaceutisk Kemi
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Hedeland, Mikael (author)
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(creator_code:org_t)
- 2006-03-15
- 2006
- English.
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In: Drug Metab Dispos. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0090-9556. ; 34:6, s. 984-92
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Abstract
Subject headings
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- 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Keyword
- Androgen Antagonists/*metabolism/therapeutic use/urine
- Animals
- Antineoplastic Agents
- Hormonal/*metabolism/therapeutic use/urine
- Biotransformation
- Chromatography
- Liquid
- Dogs
- Flutamide/*analogs & derivatives/*metabolism/standards/therapeutic
- use/urine
- Glucuronidase
- Humans
- Male
- Microsomes
- Liver/metabolism
- Prostate/metabolism
- Prostatic Neoplasms/drug therapy/*metabolism/urine
- Rats
- Spectrometry
- Mass
- Electrospray Ionization
- Swine
- Androgen Antagonists/*metabolism/therapeutic use/urine
Publication and Content Type
- ref (subject category)
- art (subject category)
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