P-Glycoprotein Effects on Drugs Pharmacokinetics and Drug-Drug- Interactions and Their Clinical Implications

Abstract

During the last couple of decades, efflux transporters have received considerable attention due to their ability to alter, either beneficially or detrimentally the pharmacokinetic and pharmacodynamic for an administered drug. The expression of the energy dependent transporter, member of the ATP binding cassette (ABC) transporters superfamily, is not only limited to cancerous tissues, but is also expressed in different normal tissues and barriers such as the blood brain barrier and placenta. Furthermore, its unique distribution at the sites of absorption such as small intestine has been shown to greatly affect the bioavailability of the drug-substrates, and thus altering their effect. In addition, the striking overlap of substrates between P-glycoprotein (P-gp) and the phase I enzyme cytochrome P450 3A4 (CYP3A4) in addition to their coexistence at the same site has been shown to act synergistically to decrease oral drug bioavailability. Interestingly, the co-administration of a drug-substrate and an inhibitor of P-gp have been shown to increase the plasma concentration of the drug-substrates causing lethal toxicities that warrants critical evaluation of drugs as whether or not they could be substrates or inhibitors to P-gp. The availability of various in vitro cell culture models and in vivo knockout models of P-gp are currently serving the pharmaceutical sciences community to deliver safer drug use and lower risks of drug-drug interactions based on P-gp interactions. Therefore, the purpose of the current review is to summarize the current knowledge about the role of P-gp in determining drug ADME profile, and its role in drug-drug-interactions and their clinical implications.

Chalcones as Promising Antitumor Agents by Targeting the p53 Pathway: An Overview and New Insights in Drug-Likeness

“…Curiously, all chalcones 56 – 80 have high probability of not being subtracts of P-gp efflux pump, in contrast to compounds 1 – 7 , which have been predicted to be subtracts of P-gp. P-gp is commonly expressed in various organs, including the BBB and brush border membrane of the small intestine [ 88 ]. The presence of this efflux pump in the brush border membrane of the small intestine may pump out orally absorbed anticancer agents and, hence, decrease the drug’s bioavailability.…”

In Silico Prediction, Molecular Docking and Dynamics Studies of Steroidal Alkaloids of Holarrhena pubescens Wall. ex G. Don to Guanylyl Cyclase C: Implications in Designing of Novel Antidiarrheal Therapeutic Strategies

“…It functions as an efflux pump and exports a large number of drugs from cells, resulting in reduced intestinal absorption and enhanced elimination into bile and urine [ 60 ]. This indicates that P-gp has a great impact on the ADME properties of a variety of drugs [ 61 , 62 ]. Therefore, it was decided to examine whether or not the test ligands were substrates for P-gp.…”

Computational Guided Approach for Drug Repurposing Against SARS-CoV-2

“…CYP450 (CYP3A4) is the main enzyme that catalyzes drug metabolism in the intestine and liver. The co-existence of CYP3A4 and Pgp at the same site synergistically reduces the bioavailability of the drug [ 62 , 63 ]. There was no overlapping observed in CYP3A4 and Pgp suggesting the high bioavailability of the tested drugs.…”