In Silico Investigation of First-Pass Effect on Selected Small Molecule Excipients and Structural Dynamics of P-glycoprotein

Abstract

In this study, the interaction of selected pharmaceutical excipients on the function of P-glycoprotein (P-gp) and activity of 6 cytochrome P450 (CYP) isoforms were computationally investigated. At binding free energy cut-off value of −5.0 kcal/mol, the result showed possible modulatory or inhibitory effect by cethyl alcohol on CPY3A4 and P-gp; cetyltrimethyl-ammonium bromide (CTAB) on CYP1A2 and P-gp; dibutyl sebacate on CYP2C9, CYP2E1, and P-gp; sodium caprylate on CYP1A2 and CYP3A4; while most of the tested excipients have good interaction with the cytochromes and P-gp. The predicted pharmacokinetics provided possible inhibitors of the CYPs and P-gp and suggested that aspartame and acetyl tributyl citrate may not permeate blood–brain barrier and not act as P-gp substrates. Target prediction for CTAB showed 100% and 35% probability of target to dynamin-1 (UniProt ID: Q05193) and histamine H3 receptor (UniProt ID: Q9Y5N1), respectively, whereas tricaprylin showed 40% probability of target to 5 Protein kinase C (UniProt IDs: P17252, Q02156, Q04759, P24723, and P05129). This study shows that synergistic effect of some excipients present in a drug formulation and multiple drugs administration is possible through modulation of CYPs activities and P-gp function, and this is crucial for consideration to mitigate toxicity in pediatric and adult populations.

ADME, Molecular Targets, Docking, and Dynamic Simulation Studies of Phytoconstituents of Cymbopogon citratus (DC.)

“…P-glycoprotein (P-gp), a membrane transporter, plays a role in drug absorption and distribution by actively pumping drugs out of cells. P-gp can influence drug bioavailability, and its inhibition or modulation is a consideration in drug development to enhance drug efficacy [25].…”

In Silico Exploration of Metabolically Active Peptides as Potential Therapeutic Agents against Amyotrophic Lateral Sclerosis

“…Permeability glycoprotein (P-gp; ABCB1; MDR1) belongs to the ATP-binding cassette (ABC) superfamily, and it is an active efflux transporter of an extensive range of xenobiotics and endogenous compounds across the cell membrane which requires expenditure of energy in terms of ATP, and it is localized in the gastrointestinal tract, BBB, kidneys, liver, and placenta of humans [ 105 , 106 ]. P-gp efflux and cytochrome P450s (CYPs) activities can greatly impact drug pharmacokinetics by clinically affecting the drug effectiveness, due to the fact that there are more than 55 CYP homologues in humans of which 90% of therapeutic ingredients are metabolized by CYP1A2, CYP2E1, CYP2C19, CYP2C9, CYP2D6, CYP3A5, and/or CYP3A4, [ 106 ]. In the ALS SOD1 G93A mouse model, damages in the BBB and micro-vessels of post-mortem spinal cord and brain tissues have been reported [ 107 ].…”

Harmine and 7,8-dihydroxyflavone synergistically suitable for amyotrophic lateral sclerosis management: An in silico study

“…Hierarchical clustering builds collectively a hierarchy of clusters based on pairwise compound similarities defined using the atom pair descriptors and the Tanimoto coefficient, and it has application in drug discovery (Sanni et al 2017). Permeability glycoprotein, also known as P-glycoprotein (P-gp; MDR1; ABCB1), is an efflux transporter, which is present in the BBB, GI tract, kidneys, liver, and placenta of humans, where it actively transports a wide range of structurally and mechanistically diverse endogenous compounds and xenobiotics across the cell membrane at the energy expense of ATP hydrolysis (Fatoki et al 2020). P-gp efflux and CYPs activity can profoundly implicate the role of BAPs pharmacokinetics by nutritionally altering their efficacy.…”

“…The molecular docking studies were carried out using the selected protein targets that have at least 90% probability and their corresponding ligands based on target prediction results, according to the method of Fatoki et al (2020). Briefly, the target proteins and ligands were prepared for docking, using AutoDock Tools (ADT) v1.5.6 (Morris et al 2009) at default settings, and the output file was saved in pdbqt format.…”