地高辛在卵巢摘除大鼠体内药动学变化研究

Study of pharmacokinetics of digoxin in ovariectomized rats model

考察地高辛(digoxin,DIG)在大鼠卵巢摘除(ovariectomy,OVX)后体内药动学变化情况,并探讨其机制。将12只SD雌性大鼠随机分为两组,即OVX组和假手术组(n=6),OVX组打开腹腔摘除双侧卵巢缝合,假手术组打开腹腔后缝合,手术后正常饲养1个月,灌胃给予地高辛(2 mg·kg^(-1))。运用液质联用(LC-MS/MS)法测定地高辛的血药浓度,并采用Western blot法测定肠道P糖蛋白(P-glycoprotein,P-gp)的表达。口服给予地高辛后,与假手术组相比,OVX组AUC0-t无显著变化,但其C_(max)较假手术组显著降低(P<0.01),OVX组的肠道P-糖蛋白的表达较假手术组具有升高趋势但无显著性差异(P>0.05)。结果表明,卵巢摘除之后大鼠地高辛的C_(max)明显降低,可能与雌激素水平降低增加P-gp表达量有关。

This study aims to investigate the change of plasma concentration of digoxin （DIG） in rats with ovariectomy. Twelve female SD rats were randomly assigned into ovariectomized group and sham group （n = 6）. All rats plasma was collected after a single dose of 2 mg.kg-1 DIG administrated orally, serum DIG concentration was determined by LC-MS/MS. The level of P-gp in the intestinal was analyzed by Western blotting. Pharmacokinetic calculations were performed on each individual using DAS 2.0 practical pharmacokinetic software. Compared with the sham group, Cmax of ovariectomized group decreased significantly （P〈0.01）. There was no significant difference of AUC0-t and the level of P-gp was elevated in ovariectomized group. It was found that Cmax of DIG was significantly reduced after ovariectomy, and the change was associated with the decreased level of estrogen, which contributes to the increased level of P-gp.