Characterization of P-Glycoprotein Inhibitors for Evaluating the Effect of P-Glycoprotein on the Intestinal Absorption of Drugs

Abstract

For developing oral drugs, it is necessary to predict the oral absorption of new chemical entities accurately. However, it is difficult because of the involvement of efflux transporters, including P-glycoprotein (P-gp), in their absorption process. In this study, we conducted a comparative analysis on the inhibitory activities of seven P-gp inhibitors (cyclosporin A, GF120918, LY335979, XR9576, WK-X-34, VX-710, and OC144-093) to evaluate the effect of P-gp on drug absorption. GF120918, LY335979, and XR9576 significantly decreased the basal-to-apical transport of paclitaxel, a P-gp substrate, across Caco-2 cell monolayers. GF120918 also inhibited the basal-to-apical transport of mitoxantrone, a breast cancer resistance protein (BCRP) substrate, in Caco-2 cells, whereas LY335979 hardly affected the mitoxantrone transport. In addition, the absorption rate of paclitaxel after oral administration in wild-type mice was significantly increased by pretreatment with LY335979, and it was similar to that in mdr1a/1b knockout mice. Moreover, the absorption rate of topotecan, a BCRP substrate, in wild-type mice pretreated with LY335979 was similar to that in mdr1a/1b knockout mice but significantly lower than that in bcrp knockout mice. These results indicate that LY335979 has a selective inhibitory activity for P-gp, and would be useful for evaluating the contribution of P-gp to drug absorption.

Oral etoposide and zosuquidar bioavailability in rats: Effect of co-administration and in vitro-in vivo correlation of P-glycoprotein inhibition

“…Although zosuquidar is not marketed as a P-gp inhibitor, it has been heavily utilised as a model inhibitor in the research of ADME properties of potential P-gp substrates. For instance, zosuquidar has commonly been applied to alter the distribution of P-gp substrates to the CNS by inhibition of P-gp mediated cellular efflux in the blood-brain barrier ( Bihorel et al, 2007 ; Chen et al, 2009 ; Choo et al, 2000 ; Dai et al, 2003 ; Karssen et al, 2002 ; Mittapalli et al, 2012 ; Nagaya et al, 2020 ) and to a lesser extent to increase the oral absorption of P-gp substrates ( Adane et al, 2012 ; Al-Ali et al, 2020 ; Bardelmeijer et al, 2004 ; Matsuda et al, 2013 ; Mouly et al, 2004 ; Kono et al, 2021 ; Tsukimoto et al, 2015 ). Recently, the influence of factors such as sex, dosing time, and food intake on P-gp expression and function in the small intestine has also been investigated ( Dou et al, 2020 ; Mai et al, 2019 ; Mai et al, 2018 ; Mai et al, 2021 ), and zosuquidar has been applied as an inhibitor in this context as well ( Kara et al, 2021 ).…”

Approaches to minimize the effects of P‐glycoprotein in drug transport: A review

“…In the mice, MDR1a & MDR1b genes are analogous to the human MDR1 gene responsible for P-gp activity in mice (Kono et al, 2021).…”

“…In the mice, MDR1a & MDR1b genes are analogous to the human MDR1 gene responsible for P‐gp activity in mice (Kono et al, 2021). The concentration of Ivermectin (87 folds) and Dexamethasone was higher in MDR1a knockout mice brain concerning wild‐type mice (Meijer et al, 1998; Schinkel et al, 1994).…”

Pharmaceutical Formulations with P-Glycoprotein Inhibitory Effect as Promising Approaches for Enhancing Oral Drug Absorption and Bioavailability

“…Third-generation inhibitors can inhibit P-gp at a low concentration (30–100 nM) and are at least 10-fold more potent than earlier inhibitors [ 107 ]. A recent study compared different P-gp inhibitors and found that LY335979 could be the most valuable inhibitor for investigations of P-gp contribution to drug absorption [ 34 ]. Novel P-gp inhibitors are still being developed and investigated [ 29 , 112 , 113 , 114 ].…”

“…In the A/J mice (an inbred albino strain of mouse model), the oral bioavailability of Rh2s was considerably increased after co-administration with cyclosporine A. In a recent study, the AUC and C max values of PTX after oral administration in mdr1a/1b (−/−) mice were 2.8−3.3 and 2.7–3.5-fold higher than those in wild-type mice, respectively [ 34 ], indicating that P-gp expressed in the intestinal epithelium restricted the intestinal absorption of PTX. In addition, the research group found that C max and AUC values of PTX after oral administration in wide-type mice were significantly increased by pretreatment with LY335979 (zosuquidar), and similar to those in mdr1a/1b (−/−) mice, proving the critical impact of P-gp inhibitors in enhancing the intestinal absorption and oral bioavailability of P-gp substrates.…”