Enhancement of drug absorption by noncharged detergents through membrane and P-glycoprotein binding

Abstract

Noncharged detergents are used as excipients in drug formulations. Until recently, they were considered as inert compounds, enhancing drug absorption essentially by improving drug solubility. However, many detergents insert into lipid membranes, although to different extents, and change the lateral packing density of membranes at high concentrations. Moreover, they bind to the efflux transporter P-glycoprotein (P-gp) and most likely to related transporters and metabolising enzymes with overlapping substrate specificities. If their affinity to P-gp is higher than that of the coadministered drug they act as modulators or inhibitors of P-gp and enhance drug absorption. Inhibition of P-gp and related proteins can, however, cause severe side effects. This paper first reviews the membrane binding propensity of different noncharged detergents (including poloxamers) and discusses their ability to bind to P-gp. Second, literature data on drug uptake enhancement by noncharged detergents, obtained in vivo and in vitro, are analysed at the molecular level. The present analysis provides the tools for an approximate and simple prior estimate of the membrane and P-gp binding ability of noncharged detergents based on a modular binding approach.

Lipid Regulation of the ABCB1 and ABCG2 Multidrug Transporters

“…Strong ionic detergents, such as SDS, may irreversibly destroy transporter function. Still, some nonionic detergents, such as Triton X-100 or C12EO8, below their CMC concentrations, have been indicated to be transported substrates of ABCB1 and possibly bind to the drug-binding site of the protein (Beck et al, 2013;Li-Blatter, Nervi, & Seelig, 2009;Seelig & Gerebtzoff, 2006;Zordan-Nudo, Ling, Liu, & Georges, 1993). Bile acids and related compounds (e.g., CHAPS) modify ABCG2 transporter function below the concentrations causing detergent effects, while some potentially "mild" detergents may have serious adverse effects.…”

Binding of an octylglucoside detergent molecule in the second substrate (S2) site of LeuT establishes an inhibitor-bound conformation

“…S1), arguing directly against low-affinity substrate binding to either site, and (iii) impairing substrate binding to the S2 site, either by mutations or binding of TCAs (17) or OG, inhibits the Na ϩ -coupled substrate symport mechanism. Interestingly, it was shown recently that noncharged detergents, including OG, are not inert compounds, because they bind to the efflux-transporter P-glycoprotein and modulate drug effects with specificities overlapping those of substrates (21). Also, OG was reported to inhibit the renal Na ϩ /glucose transporter in a competitive fashion with an IC 50 OG of ϳ10 M (22).…”

Enhancement of intestinal absorption of 2-methyl cytidine prodrugs

“…The mechanism by which sodium caprate exerts its effect as an absorption enhancer has been attributed in the literature to increasing paracellular transport through tight-junction disruption or membrane fluidization (Majumdar & Mitra, 2006) and also by inhibition of P-glycoprotein-mediated cellular efflux (Seelig & Gerebtzoff, 2006). To address if the Pgp inhibition mechanism is playing a relevant role in C1 absorption promotion, a Pgp knockout mouse model was employed (Schinkel et al, 1997).…”

“…It is well known (Seelig & Gerebtzoff, 2006) that one of the chemical classes of promoters tested, the ionic surfactants, can bind to the efflux transporter P-glycoprotein (Pgp), and most likely to related transporters, by both direct surfactant-Pgp interaction (Friche et al, 1990;Spoelstra et al, 1991;Woodcock et al, 1992;ZordanNudo et al, 1993) and membrane fluidization (Loe & Sharom, 1993;Regev et al, 1999).…”