ToxSci Advance Access originally published online on September 29, 2004
Toxicological Sciences 2004 82(2):407-418; doi:10.1093/toxsci/kfh294
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Toxicological Sciences vol. 82 no. 2 © Society of Toxicology 2004; all rights reserved.
Pharmacokinetics of Dibutylphthalate in Pregnant Rats
CIIT Centers for Health Research, 6 Davis Drive, Research Triangle Park, North Carolina 27709–2137
Received July 1, 2004; accepted September 16, 2004
Dibutylphthalate (DBP) can cause adverse effects on the developing male reproductive tract when administered late in gestation to pregnant rats. The objectives of this study were to evaluate the metabolism of DBP in female rats, and the pharmacokinetics of DBP in pregnant rats on gestational day (g.d.) 20. The identities of DBP metabolites in urine and in maternal and fetal plasma were confirmed by LC-MS/MS, as monobutylphthalate (MBP) and its glucuronide, monohydroxybutylphthalate and its glucuronide, and butanoic acid phthalate and its glucuronide. An LC-MS/MS method was developed for the quantitation of MBP and its glucuronide. MBP and MBP glucuronide were quantitated in maternal and fetal plasma, and in amniotic fluid from pregnant rats administered a single dose of DBP (50, 100, or 250 mg/kg by gavage in corn oil) on g.d. 20. The pharmacokinetics of MBP and MBP glucuronide were determined. MBP was the major metabolite in maternal and fetal plasma. With increasing dose, there was a nonlinear increase in area under the curve (AUC) for MBP, with a ten-fold increase in maternal plasma, and an eight-fold increase in fetal plasma between 50 mg/kg and 250 mg/kg. In amniotic fluid, the major metabolite initially was MBP, but by 24 h after dosing, the major metabolite was MBP glucuronide. Isomers of the MBP glucuronide were detected in amniotic fluid, suggesting acyl group migration, known to occur with acyl glucuronides. This study indicated that MBP, thought to be the active metabolite of DBP, can cross the placenta in late gestation, and that the metabolism of MBP is saturable.
Key Words: dibutylphthalate; monobutyphthalate; pharmacokinetics; pregnant rats.
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