Preclinical Transplacental Transfer and Pharmacokinetics of Fipronil in Rats

Fipronil, a widely used insecticide and pesticide, with its toxic metabolite fipronil sulfone was detected in fipronil-contaminated eggs as a result of inappropriate use. However, little is known about whether fipronil and fipronil sulfone transfer into fetus through the blood-placenta barrier. Our objectives were to investigate the transplacental transfer and the pharmacokinetics of fipronil and fipronil sulfone in rats. Male and female (with 13 days of gestation) Sprague-Dawley rats were used in pharmacokinetics and transplacental transfer experiments, respectively. Biologic samples were collected at each time point after fipronil intravenous or oral administration. To monitor fipronil and fipronil sulfone in the plasma, placenta, amniotic fluid, and fetus, a validated liquid chromatography tandem mass spectrometry method was developed. After fipronil administration in male rats, the oral bioavailability decreased, whereas the biotransformation increased as the dose increased, revealing an enhancement of first-pass effect and a fast metabolism in vivo. The results of fipronil transplacental transfer in pregnant rats demonstrated that the concentration of fipronil and fipronil sulfone varied in the following order, respectively: placenta > plasma > fetus > amniotic fluid and plasma > placenta > fetus > amniotic fluid. This is the first direct evidence that fipronil and fipronil sulfone cross the blood placental barriers and enter the fetus. The amount of fipronil distributed to the fetus was greater than that of fipronil sulfone in the short term, but by contrast, pharmacokinetic data showed that the latter stayed longer in the body. These findings provide constructive information for public health alarm. SIGNIFICANCE STATEMENT Fipronil and fipronil sulfone interfere with the GABAergic system. Fipronil can cause thyroid dysfunction, which may affect brain growth and nerve development. Although we knew that fipronil and fipronil sulfone could enter eggs, there was no direct evidence that they would enter fetuses. This research provided evidence on the pharmacokinetics and transplacental transfer of fipronil and fipronil sulfone, confirming our hypothesis.