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ToxSci Advance Access published online on September 29, 2004
Toxicological Sciences, doi:10.1093/toxsci/kfh294
Toxicological Sciences © Society of Toxicology 2004; all rights reserved
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Received July 1, 2004
Accepted September 16, 2004

Biotransformation and Toxicokinetics

Pharmacokinetics of Dibutylphthalate in Pregnant Rats

Timothy R. Fennell 1*, Wojciech L. Krol 1, Susan C. J. Sumner 1, and Rodney W. Snyder 1

1 CIIT Centers for Health Research, 6 Davis Drive, Research Triangle Park, NC 27709-2137, USA

* To whom correspondence should be addressed. E-mail: Fennell{at}rti.org.


  Abstract

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 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 non-linear increase in AUC for MBP, with a 10-fold increase in maternal plasma, and an 8-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.

Keywords: Dibutylphthalate; Monobutyphthalate; Pharmacokinetics; Pregnant Rats.
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