Pharmacokinetics and dosimetry of the antiandrogen vinclozolin after oral administration in the rat.
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.
Sierra-Santoyo
Adolfo
A
Experimental Toxicology Division, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Col. San Pedro Zacatenco, México DF, México. asierra@cinvestav
Castañeda-Hernández
Gilberto
G
Harrison
Randy A
RA
Barton
Hugh A
HA
Hughes
Michael F
MF
D000284:Administration, Oral; D000726:Androgen Antagonists / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001711:Biotransformation; D008297:Male; D008954:Models, Biological; D010080:Oxazoles / Q000008:administration & dosage* / Q000493:pharmacokinetics* / Q000633:toxicity; D051381:Rats; D020318:Rats, Long-Evans; D014018:Tissue Distribution
D000726:Androgen Antagonists; D015415:Biomarkers; D010080:Oxazoles; C025643:vinclozolin