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

Abstract

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.