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

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.