The P-glycoprotein (Pgp, ABCB1-protein) is a transport protein localized in the membrane of hepatocytes, small and large intestine enterocytes, renal tubular epitheliocytes, endothelial cells of histohematic barriers, and tumor cells. Aim — to study the effect of estradiol and progesterone physiological concentrations on the Pgp functional activity on the whole body. Material and methods. The work was performed on 17 adult female chinchilla rabbits. The first group of rabbits underwent a “false operation” (n=5); the second group (n=6) underwent ovariectomy. The third group (n=6) was ovariectomized and received estradiol (0.5 mg/rabbit) for 14 days (starting on the 14th postoperative day), followed by combined administration of estradiol (0.5 mg/rabbit) and progesterone (5 mg/rabbit) for 14 days. The Pgp functional activity was determined in rabbits of all groups using HPLC analysis of fexofenadine pharmacokinetics on day 7 before the study onset and on day 14, 28, and 42 after the operation. Accumulation of fexofenadine in rabbits indicates Pgp inhibition, and a decrease in its content means Pgp induction. Results. Ovariectomy led to a decrease in the Pgp functional activity. The estradiol introduction for 14 days after ovariectomy did not significantly affect the transport protein functional activity. Combined administration of estradiol and progesterone for 14 days resulted in an increase in the Pgp activity, compared to that in the ovariectomy series and baseline values. Conclusions. The dependence of the transport protein activity on the dynamics of physiological estradiol and progesterone concentrations suggests that the effectiveness of pharmacotherapy with Pgp substrates may depend on the menstrual cycle phase, and drug dose correction may be used to increase the pharmacotherapy effectiveness.