Exploratory Study of Sex Differences in P-Glycoprotein Function at the Blood–Brain Barrier

Abstract

Permeability-glycoprotein (P-gp), a crucial efflux pump transporter encoded by the ABCB1 gene, plays a pivotal role in drug disposition at the blood–brain barrier (BBB) and is involved in the pharmacokinetics of numerous therapeutic agents. This study investigates differences in P-gp function at the BBB between males and females in a cohort of older (55+) healthy volunteers (HV) using [¹⁸F]MC225 and PET. Twenty HV (11 males and 9 females), free from medications that affect P-gp function and without a history of neurological or psychiatric disorders, underwent [¹⁸F]MC225 PET scans with manual arterial blood sampling. Tissue time-activity curves (TAC) were extracted using the Hammers maximum-probability atlas. Whole-blood TAC was derived from the internal carotid arteries, calibrated using manual arterial samples, and adjusted for the plasma-to-whole blood ratio and plasma parent fraction to obtain the image-derived input function. The volume of distribution (V_T) was estimated using a reversible two-tissue compartment model, yielding the parameter of interest. Statistical analysis revealed no significant differences in P-gp function between sexes, based on V_T values across various brain regions (Cohen's d < 0.2). Furthermore, the arterial blood concentration, plasma parent fraction, and microparameters demonstrated no statistical differences between male and female participants. These findings suggest that P-gp function at the BBB does not exhibit substantial sex-related variability in healthy older adults (55+). For future [¹⁸F]MC225 PET studies, a mixed-sex population can serve as an appropriate age-matched control group for neurodegenerative studies. Further research is needed to explore sex-related differences in younger populations, particularly with respect to hormonal cycles.