Study Models of Drug-Drug Interactions Involving P-Glycoprotein: The Potential Benefit of P-Glycoprotein Modulation at the Kidney and Intestinal Levels

Abstract

P-glycoprotein (P-gp) is a crucial membrane transporter situated on the cell's apical surface, being responsible for eliminating xenobiotics and endobiotics. P-gp modulators are compounds that can directly or indirectly affect this protein, leading to changes in its expression and function. These modulators can act as inhibitors, inducers, or activators, potentially causing drug-drug interactions (DDIs). This comprehensive review explores diverse models and techniques used to assess drug-induced P-gp modulation. We cover several approaches, including in silico, in vitro, ex vivo, and in vivo methods, with their respective strengths and limitations. Additionally, we explore the therapeutic implications of DDIs involving P-gp, with a special focus on the renal and intestinal elimination of P-gp substrates. This involves enhancing the removal of toxic substances from proximal tubular epithelial cells into the urine or increasing the transport of compounds from enterocytes into the intestinal lumen, thereby facilitating their excretion in the feces. A better understanding of these interactions, and of the distinct techniques applied for their study, will be of utmost importance for optimizing drug therapy, consequently minimizing drug-induced adverse and toxic effects.

Keywords: P-glycoprotein; activation; ex vivo; in silico; in vitro; in vivo; induction; inhibition; kidney.

Figure 1

Schematic representation of molecules’ movement and metabolism in proximal tubular epithelial cells and enterocytes, including the transporters’ location and the direction of the substrates’ movement, involved in phases 0 and III of pharmacokinetics. Legend: ASBT: ileal apical sodium/bile acid co-transporter; BCRP: breast cancer resistance protein; blue spheres: xenobiotics; MATE: multidrug and toxin extrusion protein; MCT: monocarboxylic acid transporter; MRP: multidrug resistance protein; OAT: organic anion transporter; OATP: organic anion-transporting polypeptide; OCT: organic cation transporter; OCTN: organic cation/ergothioneine transporter; OSTα-OSTβ: heteromeric organic solute transporter; PEPT: peptide transporter; P-gp: P-glycoprotein; URAT: urate transporter; yellow spheres: xenobiotic metabolites.

Figure 2

Structural representation of the human P-glycoprotein (P-gp), a full ABC transporter, with the transmembrane domains (TMD1 in green, TMD2 in violet) containing six transmembrane α-helices (TMHs), which are linked to the respective nucleotide-binding domain (NBD1 in blue, NBD2 in pink) by coil bridges between TMH6-NB1 and TMH12-NBD2, and non-covalently by intracellular coupling helices (ICHs): ICH1 (orange)/ICH4 (dark green) and ICH2 (dark blue)/ICH3 (purple) with NBD1 and NBD2, respectively, and both connected by the linker (grey) [29]. The human P-gp model was developed in [29] and adapted to this image using Molecular Operating Environment (MOE) software (version 2019.01).

Figure 3

Schematic representation of in silico techniques currently used in the evaluation of drug–drug interactions at the P-glycoprotein level, such as ligand-based models, including the use of pharmacophores; quantitative structure–activity relationship (QSAR) models, including 3D-QSAR; and molecular dynamics simulations.

Figure 4

Representative scheme of the major cell-/membrane-based models and the major cell lines used for the in vitro evaluation of P-glycoprotein modulation.

Figure 5

Representative scheme of the major models used in the evaluation of DDIs before moving forward to clinical trials, particularly the in vivo and ex vivo models.

Figure 6

Representative scheme of the proximal tubular epithelial cells with normal, inhibited, or induced/activated P-glycoprotein.