Tamoxifen Therapy Is Associated With Altered Intestinal P-Glycoprotein Activity In Vivo

Preclinical studies suggest that tamoxifen (TAM) may interact with the efflux transporter P-glycoprotein (P-gp); however, its effect on intestinal P-gp activity in vivo remains poorly characterized. This study evaluated intestinal P-gp activity in women receiving tamoxifen therapy using fexofenadine (FEXO) as a probe substrate. Sixteen women receiving tamoxifen (20 mg/day for ≥80 days) and 12 healthy women were enrolled. All participants received a single oral dose of fexofenadine (120 mg), and serial plasma samples were collected over 12 h. Pharmacokinetic parameters were determined by noncompartmental analysis, and plasma fexofenadine concentrations were quantified by LC-MS/MS. Systemic exposure to fexofenadine was lower in women receiving tamoxifen than in healthy women. Geometric mean (95% confidence interval [CI]) AUC_0-12h was 646.55 ng.h/mL (523.50-798.52) in the tamoxifen group and 994.77 ng.h/mL (832.21-1189.07) in healthy women, whereas AUC0-∞ was 715.40 ng.h/mL (588.92-869.05) and 1123.66 ng.h/mL (919.98-1372.43), respectively (P < .05). Apparent oral clearance (CL/F) was higher in women receiving tamoxifen (167.74 vs 106.79 L/h; P < .05), whereas elimination half-life was unchanged between groups. The observed pharmacokinetic profile is consistent with reduced oral bioavailability and suggests modulation of intestinal transporter-mediated drug disposition during tamoxifen therapy. These findings may have implications for the disposition of concomitantly administered orally administered P-gp substrates and warrant further investigation in dedicated clinical pharmacology studies.