P-glycoprotein and cytochrome P450 3A4 involvement in risperidone transport using an in vitro Caco-2/TC7 model and an in vivo model

Cousein, E; Barthélémy, Christine; Poullain, Serge; Simon, Nicolas; Lestavel, Sophie; Williame, Virginie; Joiris, E; Danel, Cécile; Clavey, Véronique; Brossard, Denis; Robert, H.; Crauste–Manciet, Sylvie; Vaccher, Claude; Odou, Pascal

doi:10.1016/j.pnpbp.2007.01.028

Cited by 22 publications

(17 citation statements)

References 45 publications

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“…25,34 RISP is a known substrate of P-gp 35 and this transporter has been shown to mediate its permeability across Caco-2 cells. 36 However, our bidirectional studies did not show a difference in RISP permeability in the m-s and s-m direction, concordant with the concentration dependency studies and contrasting with what would be expected if active transport processes were involved. It is possible that active transport mechanisms were not detected in this study because the transporter was already saturated at the lowest RISP concentration.…”

Section: Discussionsupporting

confidence: 82%

The Buccal Mucosa as an Alternative Route for the Systemic Delivery of Risperidone

Heemstra

Finnin

Nicolazzo

2010

Journal of Pharmaceutical Sciences

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Section: Discussionsupporting

confidence: 82%

The Buccal Mucosa as an Alternative Route for the Systemic Delivery of Risperidone

Heemstra

Finnin

Nicolazzo

2010

Journal of Pharmaceutical Sciences

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“…In the intestine, P-gp and CYP3A are believed to work coordinately as a barrier to reduce the intracellular concentrations of xenobiotics and thus lower the intestinal absorption of drugs (Cousein et al, 2007). In cells in vitro, P-gp inhibitors increase the extent of metabolism of the parent drug by increasing its intracellular concentration and thus its availability for CYP3A (Sun and Pang, 2008).…”

Section: Introductionmentioning

confidence: 99%

The Consequence of Drug-Drug Interactions Influencing the Interplay between P-Glycoprotein and Cytochrome P450 3a: An Ex Vivo Study with Rat Precision-Cut Intestinal Slices

Graaf

Siissalo

et al. 2016

Drug Metabolism and Disposition

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P-glycoprotein (P-gp) and cytochrome P450 3A (CYP3A) are differentially expressed along the intestine and work coordinately to reduce the intracellular concentration of xenobiotics and the absorption of orally taken drugs. Drug-drug interactions (DDIs) based on P-gp/CYP3A interplay are of clinical importance and require preclinical investigation. We investigated the P-gp/Cyp3a interplay and related DDIs with different P-gp inhibitors in the various regions of the rat intestine ex vivo using precision-cut intestinal slices (PCIS) with quinidine (Qi), a dual substrate of P-gp and Cyp3a, as the probe. The results showed that P-gp efflux was the main factor limiting the intracellular Qi content at concentrations below 5 mM, whereas both efflux and metabolism were saturated at [Qi] > 50 mM. The selective P-gp inhibitors CP100356 [N-(3,4-dimethoxyphenethyl)-4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2[1H]-yl)-6,7-dimethoxyquinazolin-2-amine] and PSC833 [valspodar, 6-[(2S,4R,6E)-4-methyl-2-(methylamino)-3-oxo-6-octenoic acid]-7-Lvaline-cyclosporin A] enhanced the Qi accumulation in slices in line with the different P-gp expression in the intestinal regions and, as a result, also enhanced metabolism in the jejunum and ileum. Dual inhibitors of both P-gp and Cyp3a (verapamil and ketoconazole) increased the concentration of Qi in the jejunum and ileum, but less 3-hydroxy-quinidine was produced due to inhibition of Cyp3a. The results indicate that the P-gp/Cyp3a interplay depends on the concentration of the drug and on the intestinal region under study. Furthermore, due to the P-gp/Cyp3a interplay, DDIs can lead to remarkable changes in the intracellular concentration of both the parent drug and the metabolite, which varies among the intestinal regions and depends on the selectivity of the inhibitors, with potentially important implications for disposition and toxicity of drugs and their metabolites.

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“…Intestinal P-gp and CYP3A have been reported to reduce the intracellular concentrations of their substrates due to transmembrane efflux and metabolism, respectively (Benet et al, 1999;Hirunpanich et al, 2008). Furthermore, the residence time of a drug in the intestine increases through repeated cycles of absorption and P-gp efflux, resulting in more extensive intestinal metabolism by CYP3A (Hochman et al, 2000;Cousein et al, 2007). Therefore, a general strategy to improve oral bioavailability of a drug includes the use of inhibitors for P-gp and/or CYP3A inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Effect of pluronic P123 and F127 block copolymer on P-glycoprotein transport and CYP3A metabolism

et al. 2011

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The aim of the present study was to evaluate the effect of pluronic P123 (P123) and pluronic F127 (F127) on intestinal P-glycoprotein (P-gp) and cytochrome P450 3A using the specific substrates rhodamine-123 (R-123) and midazolam, respectively. Caco-2 cells and everted gut sacs were used as models of intestinal mucosa to assess intestinal absorption of R-123, while rat intestinal microsomes were utilized to examine the effect of P123 and F127 on in vitro midazolam metabolism. P123 and F127 were observed to increase the intracellular accumulation of R-123 in Caco-2 cells in a dose-dependent manner. P123 significantly lowered the efflux ratio of R-123 at two concentrations in Caco-2 monolayers, whereas F127 lowered the efflux ratio only at 1%. Moreover, both pluronics markedly enhanced mucosal to serosal absorption of R-123 in excised ileum of rats. However, no significant difference in relative enzyme activity were observed between P123- or F127-treated and control groups, regardless of the concentrations of P123 and F127 studied. Collectively, these results obtained from the present study demonstrated that P123 and F127 were capable of inhibiting the intestinal P-gp activity, but had little or no effect on intestinal cytochrome P450 3A activity, indicating that P123 and F127 can potentially be used as pharmaceutical ingredients to improve the oral bioavailability of coadministered P-gp substrates via P-gp efflux pump inhibition.

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P-glycoprotein and cytochrome P450 3A4 involvement in risperidone transport using an in vitro Caco-2/TC7 model and an in vivo model

Cited by 22 publications

References 45 publications

The Buccal Mucosa as an Alternative Route for the Systemic Delivery of Risperidone

The Buccal Mucosa as an Alternative Route for the Systemic Delivery of Risperidone

The Consequence of Drug-Drug Interactions Influencing the Interplay between P-Glycoprotein and Cytochrome P450 3a: An Ex Vivo Study with Rat Precision-Cut Intestinal Slices

Effect of pluronic P123 and F127 block copolymer on P-glycoprotein transport and CYP3A metabolism

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