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Pharmacokinetics and dosimetry of the anti-androgen vinclozolin after oral administration inthe rat
Citation:
Sierra-Santoyo, A., G. Castaneda-Hernandez, R. A. HARRISON, H. A. BARTON, AND M. F. HUGHES. Pharmacokinetics and dosimetry of the anti-androgen vinclozolin after oral administration inthe rat. TOXICOLOGICAL SCIENCES. Society of Toxicology, RESTON, VA, 106(1):55-63, (2008).
Impact/Purpose:
The fungicide vinclozolin is an anti-androgen. Oral administration of it to pregnant rats results in morphological feminization and demasculinization of male offspring. Similar exposure to male peripubertal rats causes delayed pubertal maturation and alters hormone levels. While a lot is known about the effects of V, there is little information on its disposition once it is absorbed in rats. We wanted to determine the pharmacokinetics of this compound after oral administration and characterize the metabolites, some ofwhich, bind to the androgen receptor. The binding to the androgen receptor by V and these metabolites is thought to be the mechanism of action for their anti-androgenic effect.
Description:
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 (t(1/2 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 t(1/2) = 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 (t(1/2 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.
