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METABOLISM AND DOSIMETRY OF VINCLOZOLIN IN RAT
SIERRA-SANTOYO, A., R. A. HARRISON, B. C. EDWARDS, M. F. HUGHES, AND H. A. BARTON. METABOLISM AND DOSIMETRY OF VINCLOZOLIN IN RAT. Presented at 45th Annual Society of Toxicology Meeting 2006, San Diego, CA, March 05 - 09, 2006.
Vinclozolin (V) is an agricultural fungicide. V administered to rats is hydrolyzed to 2-[[(3,5-dichlorophenyl)-carbamoyl]oxy]-2-methyl-3-butenoic acid (M1) and 3',5'-dichloro-2-hydroxy-2-methylbut-3-enanilide (M2). V, M1and M2 are antiandrogenic by interacting with the androgen receptor. Data on the disposition of V is limited. Our objective was to study the disposition of V in rat. Adult male LE rats were administered 100 mg/kg V in corn oil by gavage and were sacrificed over time after dosing. Blood and tissues were removed and analyzed for V and metabolites after extraction with acetonitrile by HPLC/UV. M1, M2 and four other metabolites were detected in serum. Two metabolites were identified as 3',5'-dichloro-2,3,4-trihydroxy-2-methylbutylanilide (M4) and N-(2,3,4-trihydroxy-2-methyl-1-oxo)-3,5-dicholorophenyl-1-carbamic acid (M5). At 2 h, V serum concentration peaked (16.8 lM); only trace levels were detected at 24 h ( t1/2= 3.8 h). V was detected in all tissues but preferentially accumulated in fat (182.8 lg/g). M1 serum levels increased until 8 h (43 lM), were at least 2-fold higher than those of
V, and then declined with a t1/2 = 3.4 h. M4 was the most abundant metabolite in serum and tissues except fat. Serum M4 levels were at least 5-fold higher than V levels and 2-fold greater than M1 at all times. At 48 h, M4 was the main metabolite in serum (t1/2= 12.6 h) and was detected in all tissues. Liver and kidney exhibited the highest levels of M4, V and M1. The two unidentified V metabolites had similar serum levels to those of V, their t1/2 were 6.9 and 8.9 h and were detected mainly in liver and kidney. M2 and M3 had the lowest levels of V metabolites in serum and tissues. In male LE rats, V is well absorbed, is extensively metabolized and widely distributed. M4, 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. (Funded in part by NRC CR 828790. This abstract does not represent USEPA policy).