Clinical Implications of P-Glycoprotein Modulation in Drug–Drug Interactions

Abstract

Drug-drug interactions (DDIs) occur commonly and may lead to severe adverse drug reactions if not handled appropriately. Considerable information to support clinical decision making regarding potential DDIs is available in the literature and through various systems providing electronic decision support for healthcare providers. The challenge for the prescribing physician lies in sorting out the evidence and identifying those drugs for which potential interactions are likely to become clinically manifest. P-glycoprotein (P-gp) is a drug transporting protein that is found in the plasma membranes in cells of barrier and elimination organs, and plays a role in drug absorption and excretion. Increasingly, P-gp has been acknowledged as an important player in potential DDIs and a growing body of information on the role of this transporter in DDIs has become available from research and from the drug approval process. This has led to a clear need for a comprehensive review of P-gp-mediated DDIs with a focus on highlighting the drugs that are likely to lead to clinically relevant DDIs. The objective of this review is to provide information for identifying and interpreting evidence of P-gp-mediated DDIs and to suggest a classification for individual drugs based on both in vitro and in vivo evidence (substrates, inhibitors and inducers). Further, various ways of handling potential DDIs in clinical practice are described and exemplified in relation to drugs interfering with P-gp.

Baicalin reduces ciclosporin bioavailability by inducing intestinal p-glycoprotein in rats

“…In addition to CYP3A4 and CYP3A5, the efflux transporter P‐gp also plays a major role in the pharmacokinetics of CsA . P‐gp localizes in the polarized epithelial cells of excretory organs such as the liver, kidney and intestine to eliminate compounds . So the oral bioavailability of CsA available for immunosuppression within these cells may be influenced by their P‐gp content.…”

“…[25] P-gp localizes in the polarized epithelial cells of excretory organs such as the liver, kidney and intestine to eliminate compounds. [26] So the oral bioavailability of CsA available for immunosuppression within these cells may be influenced by their P-gp content. For instance, verapamil increased the AUC of CsA about 13% via P-gp inhibition, and rifampicin decreased the plasma concentrations of CsA approximately 60% through activating P-gp.…”

Propafenone analogue with additional H‐bond acceptor group shows increased inhibitory activity on P‐glycoprotein

“…1-Benzyl-4-piperidone 10 was used as a starting material to synthesize 4-methyl-4-phenylpiperidine (2c). The addition of methyllithium to 10 gave 1-benzyl-4-methylpiperidine-4-ol (11), which was activated by aluminum chloride and reacted with benzene to yield the Friedel-Crafts alkylation product 12. Finally, the protective group was removed by catalytic transfer hydrogenation in accordance with Salon et al [28] to give 4-methyl-4-phenylpiperidine (2c).…”

“…Co‐administration of a transported drug and a P‐gp inhibitor can lead to elevated drug levels in the plasma and in the organs defended by blood–tissue barriers, which poses the risk of organ toxicity . On this account, both the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) recommend drug candidates to be routinely screened for their capacity to inhibit P‐gp and the analogous breast cancer‐resistant protein BCRP …”

“…capacity to inhibit P-gp and the analogous breast cancer-resistant protein BCRP. [9][10][11] Over the past four decades, a considerable effort has been made to characterize the molecular basis of the interaction between P-gp and its inhibitors. [12,13] Although within analogous sets of compounds (e. g. propafenone, tetrahydroisoquinoline, tariquidar and chalcone derivatives, alkaloids, and flavonoids), a clear structure-activity relationship (SAR) pattern was observed, a general and conclusive model is still missing.…”