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Influence of female hormones on the P-glycoprotein functioning

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Abstract


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.


Alexey V. Shchulkin

Ryazan State Medical University

Author for correspondence.
Email: alekseyshulkin@rambler.ru
ORCID iD: 0000-0003-1688-0017
SPIN-code: 2754-1702

Russian Federation, 9, Vysokovoltnaja, Ryazan, 390026

MD, PhD

Ivan V. Chernykh

Ryazan State Medical University

Email: ivchernykh88@mail.ru
ORCID iD: 0000-0002-5618-7607
SPIN-code: 5238-6165

Russian Federation, 9, Vysokovoltnaja, Ryazan, 390026

PhD

Pavel Yu. Mylnikov

Ryazan State Medical University

Email: dukeviperlr@gmail.com
ORCID iD: 0000-0001-7829-2494
SPIN-code: 8503-3082

Russian Federation, 9, Vysokovoltnaja, Ryazan, 390026

Dmitry O. Utkin

Regional clinical Oncological Dispensary

Email: riverflow49@gmail.com
ORCID iD: 0000-0002-6620-2073
SPIN-code: 2368-7127

Russian Federation, Ryazan

Elena N. Yakusheva

Ryazan State Medical University

Email: e.yakusheva@rzgmu.ru
ORCID iD: 0000-0001-6887-4888
SPIN-code: 2865-3080

Russian Federation, 9, Vysokovoltnaja, Ryazan, 390026

MD, PhD, professor

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Supplementary files

Supplementary Files Action
1. Fig. 1. Concentration of estradiol in the sera of rabbits after ovariectomy and subsequent administration of a combination of estradiol and progesterone. The data are presented in the form of a median, upper and lower quartiles. View (32KB) Indexing metadata
2. Fig. 2. Concentration of progesterone in the sera of rabbits after ovariectomy and subsequent administration of a combination of estradiol and progesterone. The data are presented in the form of a median, upper and lower quartiles. View (20KB) Indexing metadata

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Copyright (c) 2018 Shchulkin A.V., Chernykh I.V., Mylnikov P.Y., Utkin D.O., Yakusheva E.N.

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