ToxSci Advance Access published online on August 14, 2008
Toxicological Sciences, doi:10.1093/toxsci/kfn167
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Pharmacokinetics and dosimetry of the anti-androgen vinclozolin after oral administration in the rat
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* Experimental Toxicology Division, National Health and Environmental Effects Research Laboratory
National Center for Computational Toxicology, Office of Research and Development, U.S. Environmental Protection Agency, MD-B143-05, 109 T.W. Alexander Drive, Research Triangle Park, NC 27711, USA
Sección Externa de Toxicología
Sección Externa de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Av. IPN No. 2508, Col. San Pedro Zacatenco, México, D.F. CP 07360, México
1 Corresponding author: Adolfo Sierra-Santoyo, 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. Telephone: (52) 55 57473800, ext 5425. Fax: (52) 55 57473395. E-mail: asierra{at}cinvestav.mx
Received June 9, 2008; revision received July 31, 2008; accepted August 2, 2008
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Abstract |
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Vinclozolin (V) is a fungicide with anti-androgenic 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 HPLC/DAD/MS. 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 (M3) 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; anti-androgenic; dicarboximides; biomarkers.
asierra{at}cinvestav.mx, gcastaneda{at}cinvestav.mx, harrison.randy{at}epa.gov, barton.hugh{at}epa.gov, hughes.michaelf{at}epa.gov