Potential P-Glycoprotein-Mediated Drug-Drug Interactions of Antimalarial Agents in Caco-2 cells

Oga, Enoche Florence; Sekine, Satoshi; Shitara, Yoshihisa; Horie, Toshiharu

doi:10.4269/ajtmh.2012.11-0817

Cited by 14 publications

(13 citation statements)

References 30 publications

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“…The results showed the suitability of these two cell monolayer models to investigate P-gp function in vitro and exhibited similar basic transport characteristics of digoxin compared to data from several reports [37,38] . Although there are well-documented reports on the use of PMA to induce the PKC signaling pathway and its potent effect on drug resistance in cancer cells, this is the first report to investigate the effect of PKC activation by PMA on the P-gp-mediated efflux of digoxin using the Caco-2 and MDCKII-MDR1 cell transport models.…”

Section: Discussionsupporting

confidence: 58%

Phorbol 12-myristate 13-acetate inhibits P-glycoprotein-mediated efflux of digoxin in MDCKII-MDR1 and Caco-2 cell monolayer models

Huang

et al. 2013

Acta Pharmacol Sin

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Aim: To investigate the effects of phorbol 12-myristate 13-acetate (PMA), a PKC activator, on P-glycoprotein-mediated efflux of digoxin in two cell transport models. Methods: Caco-2 cells, wild MDCKII cells (MDCKII-WT) and MDCKII cells transfected stably with human MDR1-gene encoding P-gp (MDCKII-MDR1) were examined. Cell viability was evaluated with MTT assay. Bidirectional transport of digoxin was evaluated in these cells. Intracellular ATP level was measured using ATP assay. P-gp ATPase activity was analyzed using a Pgp-Glo TM assay. Results: PMA (10 μmol/L) did not reduce the viability of the 3 types of cells. In Caco-2 and MDCKII-MDR1 cell monolayers, PMA (1, 10 and 100 nmol/L) dose-dependently inhibited the basolateral to apical transport of digoxin, but did not change the apical to basolateral transport. In addition, PMA did not affect both the basolateral to apical and apical to basolateral transport of digoxin in MDCKII-WT cell monolayer. In agreement with the above results, PMA dose-dependently reduced intracellular ATP level and stimulated P-gp ATPase activity in both Caco-2 and MDCKII-MDR1 cells. Verapamil (a positive control, 100 μmol/L) caused similar inhibition on digoxin efflux as PMA did, whereas 4α-PMA (a negative control, 100 nmol/L) had no effect. Conclusion: PMA significantly inhibited P-gp-mediated efflux of digoxin in both Caco-2 and MDCKII-MDR1 cell monolayers via PKC activation.

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Section: Discussionsupporting

confidence: 58%

Phorbol 12-myristate 13-acetate inhibits P-glycoprotein-mediated efflux of digoxin in MDCKII-MDR1 and Caco-2 cell monolayer models

Huang

et al. 2013

Acta Pharmacol Sin

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“…42,43 Interestingly, in patients receiving NVP-based ART, the defective variant ABCB1 3435 TT genotype was significantly associated with high lumefantrine plasma concentration. Similarly, a previous study reported nonsignificant increase of lumefantrine clearance (13%) in carriers of homozygous wild type for CYP3A5*3.…”

Section: Discussionmentioning

confidence: 97%

CYP2B6*6 genotype and high efavirenz plasma concentration but not nevirapine are associated with low lumefantrine plasma exposure and poor treatment response in HIV-malaria-coinfected patients

et al. 2015

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We investigated the influence of efavirenz (EFV)- or nevirapine (NVP)-based antiretroviral therapy (ART) on lumefantrine plasma exposure in HIV-malaria-coinfected patients and implication of pharmacogenetic variations. A total of 269 HIV patients with uncomplicated falciparum malaria on NVP-based ART (NVP-arm), EFV-based ART (EFV-arm) or not receiving ART (control-arm) were enrolled and treated with artemether-lumefantrine. Day-7 lumefantrine, baseline EFV and NVP plasma concentrations, and CYP2B6*6,*18, CYP3A4*1B, CYP3A5*3,*6,*7, ABCB1 c.3435C>T and ABCB1 c.4036A>G genotypes were determined. The median day-7 lumefantrine plasma concentration was significantly lower in the EFV-arm compared with that in NVP- and control-arm. High EFV plasma concentrations and CYP2B6*6/*6 genotype significantly correlated with low lumefantrine plasma concentrations and high rate of recurrent parasitemia. No significant effect of NVP-based ART on lumefantrine exposure was observed. In conclusion, owing to long-term CYP3A induction, EFV-based ART cotreatment significantly reduces lumefantrine plasma exposure leading to poor malaria treatment response, which is more pronounced in CYP2B6 slow metabolizers.

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“…The P-gp, membrane transporter protein, has a crucial role in the modulation of absorption, distribution, metabolism and excretion of drugs. P-gp is also known to function as a barrier protein to extrude toxins and xenobiotics from cells (4,5). P-gp is able to efflux various anticancer drugs out of the cells in order to decrease the intracellular accumulation of cytostatic drugs, including doxorubicin and paclitaxel (5).…”

Section: Introductionmentioning

confidence: 99%

Effect of five novel 5‑substituted tetrandrine derivatives on P‑glycoprotein‑mediated inhibition and transport in Caco‑2 cells

Cao

Liu

et al. 2018

Oncol Lett

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Tetrandrine (Tet) is a potent inhibitor that reverses P-glycoprotein-mediated multidrug resistance (MDR). A number of novel 5-substituted tetrandrine derivatives were synthesized by the authors. The present study aimed at identifying potential P-gp inhibitor candidates, and intracellular uptake and efflux experiments and Caco-2 cell-based Transwell transport studies were performed. It was demonstrated that all five test compounds were able to inhibit efflux and increase intracellular uptake of the P-gp substrate, rhodamine-123 (Rho-123); the test compounds were P-gp inhibitors. The transepithelial transport experiment indicated that the secretory (basolateral-to-apical) of Rho-123 decreased, the absorption (apical-to-basolateral) increased and the transport efflux ratio (ER) reduced in the presence of the five compounds. Among the compounds, fluobenzene-Tet (TF) exhibited similar inhibitory effect as Tet. Although the other four test compounds exhibited weaker inhibitory effects than Tet and TF, the compounds exhibited stronger inhibitory effects compared with the reference compound verapamil. The study demonstrated that the five novel 5-substituted tetrandrine derivatives are able to act as inhibitors of P-gp to overcome P-gp-mediated drug resistance.

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Potential P-Glycoprotein-Mediated Drug-Drug Interactions of Antimalarial Agents in Caco-2 cells

Cited by 14 publications

References 30 publications

Phorbol 12-myristate 13-acetate inhibits P-glycoprotein-mediated efflux of digoxin in MDCKII-MDR1 and Caco-2 cell monolayer models

Phorbol 12-myristate 13-acetate inhibits P-glycoprotein-mediated efflux of digoxin in MDCKII-MDR1 and Caco-2 cell monolayer models

CYP2B6*6 genotype and high efavirenz plasma concentration but not nevirapine are associated with low lumefantrine plasma exposure and poor treatment response in HIV-malaria-coinfected patients

Effect of five novel 5‑substituted tetrandrine derivatives on P‑glycoprotein‑mediated inhibition and transport in Caco‑2 cells

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