The Impact of P‐Glycoprotein on CNS Drug Efflux and Variability in Response

ABSTRACT Resistance against CNS drugs may arise from various mechanisms, with limited drug penetration across the blood‐brain barrier (BBB) being a significant contributing factor. The BBB employs efflux transporters like P‐glycoprotein (P‐gp) to safeguard the brain by removing toxins and xenobiotics, however, P‐gp also pumps out therapeutic drugs, and its upregulation in disease states can contribute to variability in drug response. While inhibiting P‐gp to prevent drug efflux seems appealing, it could lead to toxicity since P‐gp is also important for expulsion of toxins from the brain. This necessitates the incorporation of P‐gp substrate liability assessment into early drug discovery stages using appropriate experimental approaches. Therefore, this review aims to draw interest in this crucial area by analyzing the existing research on P‐gp's impact on brain distribution of major CNS drugs and exploring the detection methods for identifying P‐gp substrates. By identifying confirmed P‐gp substrates and evaluating effective detection methods, this work emphasizes the continued importance of monitoring P‐gp‐mediated CNS drug efflux out of the brain tissue. This knowledge can empower clinicians to anticipate potential treatment inefficacy and guide therapeutic decision‐making, ultimately leading to improved patient treatment outcomes.