氟诺哌齐对新西兰家兔胚胎-胎仔发育毒性及毒代动力学OACSTPCD

OBJECTIVE To study the effect of fluoropezil on embryo-fetal developmental toxicity and toxicokinetics in rabbits,and provide reference for clinical medication.METHODS According to the sequence of pregnancy,pregnant rabbits were divided into five groups:vehicle control group(1%hydroxy-propyl methylcellulose+1.5%polyethylene glycol 400 aqueous solution),positive control group(cyclo-phosphamide 18 mg·kg-1),and fluoropezil(3.6,9.0 and 22.5 mg·kg-1)groups.The vehicle control group and the fluoropezil groups were ig administrated on the 6th to 18th day of gestation(GD6-18)while the positive control group was ig given cyclophosphamide on GD6-20.The pregnant rabbits were sacri-ficed on GD28,and the embryo-fetal development was detected.Sex hormone levels of pregnant rabbits on GD5,GD18 and GD28 were detected by ELISA method.Blood samples with toxokinetics were collected for concomitant toxic generation at the first and last administration,and drug concentrations in fetal,placenta and amniotic fluid were detected with liquid chromatography tandem mass spectrometry(LC-MS/MS).RESULTS Fluoropezil 3.6,9.0 and 22.5 mg·kg-1 had no significant effect on body mass,mass gain,food consumption,pregnancy outcomes,fetal appearance,viscera,skeletal and physical growth and development of pregnant rabbits.Only on GD18 or GD28,the levels of follicle stimulating hormone,estra-diol and progesterone in each dose group fluctuated to some extent.The combined toxokinetics results indicated that fluoropezil could cross the placental barrier of the rabbits,but did not accumulate in preg-nant rabbits or fetuses.Fetal mass,crown-rump length and uterus mass in the cyclophosphamide group were lower than those in the vehicle control group.The appearance and bone of the cyclophos-phamide group were positive.CONCLUSION The no observed adverse effect level(NOAEL)of fluoro-pezil toxicity on rabbit embryo-fetal development is 22.5 mg·kg-1,which is 125 times of the effective dose.At the dosage level of 22.5 mg·kg-1,Cmax is 1093 μg·L-1,and AUC(0-24 h)6650 μg·h·L-1 on GD18.