The Intestinal Efflux Transporter Inhibition Activity of Xanthones from Mangosteen Pericarp: An In Silico, In Vitro and Ex Vivo Approach

Abstract

The capacity of α-mangostin (α-MG) and β-mangostin (β-MG) from mangosteen pericarp on P-glycoprotein (Pgp) in silico, in vitro, and ex vivo was investigated in this study. Screening with the ADMET Predictor™ program predicted the two compounds to be both a Pgp inhibitor and Pgp substrate. The compounds tended to interact with Pgp and inhibit Pgp ATPase activity. Additionally, bidirectional transport on Caco-2 cell monolayers demonstrated a significantly lower efflux ratio than that of the control (α-(44.68) and β-(46.08) MG versus the control (66.26); p < 0.05) indicating an inhibitory effect on Pgp activity. Test compounds additionally revealed a downregulation of MDR1 mRNA expression. Moreover, an ex vivo absorptive transport in everted mouse ileum confirmed the previous results that α-MG had a Pgp affinity inhibitor, leading to an increase in absorption of the Pgp substrate in the serosal side. In conclusion, α- and β-MG have the capability to inhibit Pgp and they also alter Pgp expression, which makes them possible candidates for reducing multidrug resistance. Additionally, they influence the bioavailability and transport of Pgp substrate drugs.

Effect of Water Extract of Mangosteen Pericarp on Donepezil Pharmacokinetics in Mice

“…Spieler et al [60] reported that donepezil concentration in the brain and the cerebrum to plasma ratio of donepezil were increased in P-glycoprotein (P-gp) deficient mice compared to control, indicating that the brain bioavailability of donepezil depends on P-gp. Considering that numerous reports the inhibitory effects of mangosteen pericarp extract and xanthones as main components of mangosteen pericarp extract against P-gp [61,62], the increased donepezil concentration in the brain may be due to the inhibition of P-gp-mediated donepezil efflux through BBB by WMP. Although P-gp is expressed in many other organs, the degree of P-gp inhibition by P-gp inhibitors are different because the concentrations of P-gp inhibitor in the specific tissue are various, with different inhibiting P-gp activities [61,63,64].…”

“…Considering that numerous reports the inhibitory effects of mangosteen pericarp extract and xanthones as main components of mangosteen pericarp extract against P-gp [61,62], the increased donepezil concentration in the brain may be due to the inhibition of P-gp-mediated donepezil efflux through BBB by WMP. Although P-gp is expressed in many other organs, the degree of P-gp inhibition by P-gp inhibitors are different because the concentrations of P-gp inhibitor in the specific tissue are various, with different inhibiting P-gp activities [61,63,64]. In this view, WMP might significantly inhibit only P-gp mediated donepezil efflux through BBB, not in the intestine.…”

Evaluation of the Intestinal Permeability of Rosmarinic Acid from Thunbergia laurifolia Leaf Water Extract in a Caco-2 Cell Model

“…Intestinal transporter proteins and metabolizing enzymes work together and have crucial roles in regulating the oral absorption of various xenobiotics. In Caco-2 cell monolayers, the transporter proteins, efflux proteins, and metabolic phase II conjugation enzymes are available [29][30][31]. Moreover, the Caco-2 cell model can be used to determine the transport mechanism.…”

A Genetic and Immunohistochemical Analysis ofH. PyloriPhenotypes and p27 expression in Adenocarcinoma Patients in Jordan

“…GGA GCC CCA GGA AAC ATT G-3' 5'-CAT AAC TAG CGC CTT GCA C-3ATG GAA ATA CAA CAA ACA CAC-3' 5'-CTG CTT GAA TGC GCC AAA C-3CTC CAA GGA GTA AGA CC-3′ 5′-CCC CTC TTC AAG GGG TCT AC-3′157[31] …”

“…AAT ACA CCA ACG CCT CCA AG-3' 5'-TTG TTG CCG CTT TTG CTC TC-3ATG GAA ATA CAA CAA ACA CAC-3' 5'-CTG CTT GAA TGC GCC AAAC-3GGT CAA AAT GCG GTC ATG G-3' 5'-CCA TTG GTA CCT GTA GAA AC-GGA GCC CCA GGA AAC ATT G-3' 5'-CAT AAC TAG CGC CTT GCA C-3ATG GAA ATA CAA CAA ACA CAC-3' 5'-CTG CTT GAA TGC GCC AAA C-3CTC CAA GGA GTA AGA CC-3′5′-CCC CTC TTC AAG GGG TCT AC-3′ 157[31] …”