A Systematic Review and Classification of the Effects of P-glycoprotein Inhibitors and Inducers in Humans, Using Digoxin, Fexofenadine, and Dabigatran as Probe Drugs.

P-glycoprotein is a critical efflux transporter that may significantly affect the pharmacokinetics of various drugs by influencing their absorption, distribution and elimination. While European and American regulatory guidelines provide lists of P-glycoprotein modulators, they lack specificity concerning in vivo studies and clear guidance on inducers, creating uncertainty in their clinical relevance. A systematic search on in vivo clinical studies involving healthy volunteers using fexofenadine, dabigatran and digoxin as P-glycoprotein substrates has been performed in accordance with the PRISMA guidelines. A total of 151 studies assessing the impact of P-glycoprotein modulators on the concentration-time profile of P-glycoprotein substrates were retrieved. Additionally, data on the P-glycoprotein modulators' effect on cytochrome P450 3A4 induction or inhibition were also collected. P-gp modulators were classified as potent, moderate, weak or non-interactors for P-glycoprotein, with or without cytochrome P450 3A4 impact, on the basis of the area under the concentration-time curve ratio. This classification was adapted from the Food and Drug Administration criteria for cytochrome interactions. This systematic review identified 49 area under the plasma concentration-time curve ratio values corresponding to P-glycoprotein inhibitors, 23 to P-glycoprotein inducers and 131 to non-interactors. Of these, only 32.5% and 41.1% were classified as weak to potent, respectively. Only 0.7% of inhibitors and no inducers were classified as potent. This suggests that most P-glycoprotein modulators have a limited impact on drug exposure. The potential for interaction increases when P-glycoprotein modulators also affect cytochrome P450 3A4, which is the case for 59.9% of P-glycoprotein modulators. However, some moderate P-glycoprotein modulators may have clinically significant effects depending on the therapeutic margin of the substrate and the clinical context.