ToxSci Advance Access originally published online on August 14, 2008
Toxicological Sciences 2008 106(1):55-63; doi:10.1093/toxsci/kfn167
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Pharmacokinetics and Dosimetry of the Antiandrogen Vinclozolin after Oral Administration in the Rat
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* Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory
Sección Externa de Toxicología
Sección Externa de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Col. San Pedro Zacatenco, México D.F. CP 07360, México
National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, North Carolina 27711
1 To whom correspondence should be addressed at Centro de Investigación y de Estudios Avanzados del IPN (Cinvestav-IPN), Sección Externa de Toxicología, Av. IPN No. 2508, Col. San Pedro Zacatenco, México D.F. CP 07360, México. Fax: +52-55-57473395. E-mail: asierra{at}cinvestav.mx.
Received June 9, 2008; accepted August 2, 2008
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Abstract |
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Vinclozolin (V) is a fungicide with antiandrogenic properties. To determine the pharmacokinetics and dosimetry of V, adult male rats were administered an oral dose of V (100 mg/kg) in corn oil and sacrificed over time after dosing. V and its metabolites were analyzed in serum and tissues by high performance liquid chromatography/diode array detector/mass spectrometer. V, 2-[[(3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid (M1), and 3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide (M2), and five other metabolites were detected in serum and tissues. One metabolite was identified as 3',5'-dichloro-2,3,4-trihydroxy-2-methylbutylanilide (M5). The mean serum concentration data for V were fitted to a one-compartment model for kinetic analysis. At 2 h, V serum concentration peaked; whereas only trace levels were detected at 24 h (t1/2 elim = 3.6 h). V was detected in all tissues and preferentially accumulated in fat. M1 serum levels increased until 8 h, being at least 2-fold higher than those of V at this time, and then declined with a t1/2 = 3.3 h. M5 was the main metabolite in serum and tissues. Serum M5 levels were 5-fold higher than V and 2-fold greater than M1 at all times. At 48 h, M5 remained the main metabolite (t1/2 elim = 13.1 h). Liver and kidney exhibited the highest levels of M5, V, and M1. M2 and 3,5-dichloroaniline had the lowest levels of V metabolites in serum and tissues. V is well absorbed, extensively metabolized and widely distributed. M5, the most abundant V metabolite, may be used as an exposure biomarker for pharmacokinetic modeling. These results may clarify the relationship between toxicity and tissue dose of V and its metabolites.
Key Words: vinclozolin; antiandrogenic; dicarboximides; biomarkers.