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. 2024 Jan;17(1):e13713.
doi: 10.1111/cts.13713.

Intestinal P-gp activity is reduced in postmenopausal women under breast cancer therapy

Joao Paulo B Ximenez  1 , Jurandyr Moreira de Andrade  2 , Adriana Rocha  1 , Eduardo Barbosa Coelho  2 , Guilherme Suarez-Kurtz  3 , Vera Lucia Lanchote  1
Affiliations

Intestinal P-gp activity is reduced in postmenopausal women under breast cancer therapy

Joao Paulo B Ximenez et al. Clin Transl Sci. 2024 Jan.

Abstract

Intestinal P-glycoprotein (P-gp) activity plays a crucial role in modulating the oral bioavailability of its substrates. Fexofenadine has commonly been used as a P-gp probe, although it is important to note the involvement of other drug transporters like, OATP1B1, OATP1B3, and OATP2B1. In vitro studies demonstrated an upregulation of P-gp protein in response to exposure to pregnancy-related hormones. The objective of this study was to investigate how intestinal P-gp activity is impacted by menopausal status. This study sampled fexofenadine plasma concentrations over 0-12 h after probe drug administration from two groups of patients with breast cancer: premenopausal (n = 20) and postmenopausal (n = 20). Fexofenadine plasma concentrations were quantified using liquid-chromatography tandem mass spectrometry. Area under the plasma concentration-time curve from zero to infinity (AUCinf ) was calculated through limited sampling strategies equation. Multiple linear regression was applied on AUCinf , maximum plasma concentration (Cmax ), and time to Cmax . Postmenopausal patients showed a significant increase in Cmax (geometric mean and 95% confidence interval [CI] 143.54, 110.95-176.13 vs. 223.54 ng/mL, 161.02-286.06 and in AUCinf 685.55, 534.98-878.50 vs. 933.54 ng·h/mL 735.45-1184.99) compared to premenopausal patients. The carriers of the ABCB1 3435 allele T displayed higher Cmax values of 166.59 (95% CI: 129.44-214.39) compared to the wild type at 147.47 ng/mL (95% CI: 111.91-194.34, p = 0.02). In postmenopausal individuals, the decrease in P-gp activity of ~40% may lead to an increased plasma exposure of orally administered P-gp substrates.

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Conflict of interest statement

The authors declared no competing interests for this work.

Figures

FIGURE 1
FIGURE 1
Violin plot of the AUC (panel a), C max (panel b), and concentration‐time profile (panel c) of fexofenadine following an oral single‐dose (120 mg/day) in breast cancer patients (n = 40) stratified by hormonal status. Pre/postmenopausal ratio of fexofenadine pharmacokinetics parameters (panel d). AUC, area under the plasma concentration‐time curve; C max, maximum plasma concentration; LSS, limited sampling strategy; PK, pharmacokinetic; T max, time to C max.
FIGURE 2
FIGURE 2
Violin plot of the AUC (panel a), C max (panel b), and concentration‐time profile (panel c) of fexofenadine following an oral single‐dose (120 mg/day) in patients with breast cancer (n = 40) stratified by ABCB1 3435C>T genotype. ABCB1 3435C>T genotype ratio of fexofenadine pharmacokinetics parameters (panel d). AUC, area under the plasma concentration‐time curve; C max, maximum plasma concentration.
FIGURE 3
FIGURE 3
Violin plot of the AUC (panel a) and C max (panel b) of fexofenadine following an oral single‐dose (120 mg/day) in patients with breast cancer (n = 40) stratified by ABCB1 diplotype. AUC, area under the plasma concentration‐time curve; C max, maximum plasma concentration; LSS, limited sampling strategy; PK, pharmacokinetic; T max, time to C max.
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