Effect of estradiol on P-glycoprotein functional activity in experiment

Abstract

The aim of the study was to evaluate the P-glycoprotein functional activity after ovariectomy followed by estradiol treatment. Methods. The study was conducted on 23 Chinchilla rabbits weighing 4300—4700 g. Group 1 underwent a sham surgery; Group 2 was ovariectomized; Groups 3 and 4 underwent ovariectomy followed by oral estradiol treatment (0.5 mg and 2 mg, respectively). On day 7 prior to the experiment and on days 14, 28, and 42 after the surgery, P-glycoprotein functional activity was determined in rabbits of all groups by measuring fexofenadine pharmacokinetics using HPLC and serum concentrations of sex hormones (estradiol, progesterone, testosterone) using the radio immune method. Results. Ovariectomy decreased the P-glycoprotein functional activity as evident from changes in the fexofenadine pharmacokinetics — increased Cₘₐₓ and AUC₀₋ₜ and decreased Cl. The estradiol administration at a dose of 0.5 mg for 28 days after ovariectomy increased the P-glycoprotein functional activity compared to the ovariectomy group; however, the P-glycoprotein functional activity remained lower than at baseline. The estradiol treatment at a dose of 2 mg after ovariectomy increased the P-glycoprotein functional activity compared to the ovariectomy group and restored the P-glycoprotein functional activity to the value for intact animals. No correlations were found between the maintenance of estradiol content and the P-glycoprotein functional activity. Conclusion. The treatment with low-dose estradiol stimulated Pgp at the level of a whole body but was not sufficient to restore its original activity. Perhaps, for a complete recovery of the Pgp functional activity to the baseline level, additional administration of progesterone is required. When estradiol was administered at a high dose the Pgp activity increased to the baseline, preoperative level even without normalization of the progesterone content.