Inhibition of P-glycoprotein, multidrug resistance-associated protein 2 and cytochrome P450 3A4 improves the oral absorption of octreotide in rats with portal hypertension

Sun, Xiaoyu; Duan, Zhijun; Liu, Zhen; Tang, Shunxiong; Li, Yang; He, Shou‑Cheng; Wang, Qiuming; Chang, Qingyong

doi:10.3892/etm.2016.3808

Cited by 5 publications

(5 citation statements)

References 29 publications

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“…The intestinal absorption of drugs was affected by numerous factors, such as transporters, and intestinal microflora [37]. However, the scope of this study sought to focus on the permeability features of CAPB and CAPC, along with the major transporters and metabolic enzymes in intestinal epithelium including P-gp, MRP2 and CYP3A4 [5,13]. While previous studies have already evaluated the pharmacokinetics, distribution, intestinal metabolism, and excretion of CAPB and CAPC [31,32,33,34], the absorption characteristics of CAPB and CAPC in the intestinal tract were largely unknown.…”

Section: Discussionmentioning

confidence: 99%

“…Aside from ABC transporters, drug metabolism enzymes are also critical factors in determining the bioavailability of drugs, among which the cytochrome P450 enzyme (CYP450) plays a major role [13]. The CYP3A4 subset of CYP450 accounts for 30% of the total CYP450 enzyme system [14,15] and is responsible for the bio-transformation of several drugs with a key role in pharmacological effects.…”

Section: Introductionmentioning

confidence: 99%

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In Vitro and In Situ Characterization of the Intestinal Absorption of Capilliposide B and Capilliposide C from Lysimachia capillipes Hemsl

Zhang

Cheng

et al. 2019

Molecules

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The goal of this investigation was to determine the processes and mechanism of intestinal absorption for capilliposide B (CAPB) and capilliposide C (CAPC) from the Chinese herb, Lysimachia capillipes Hemsl. An analysis of basic parameters, such as drug concentrations, time, and behavior in different intestinal segments was analyzed by liquid chromatography-tandem mass spectrometry (LC-MS). The susceptibility of CAPB and CAPC to various inhibitors such as P-glycoprotein (P-gp) inhibitor (verapamil); multidrug resistance-associated protein 2 (MRP2) inhibitor (indomethacin); cytochrome P450 protein 3A4 (CYP3A4) inhibitor (ketoconazole); and the co-inhibitor of P-gp, MRP2 and CYP3A4 (cyclosporine A) were assessed using both caco-2 cell monolayer and single-pass intestinal perfusion (SPIP) models. As a result, CAPB and CAPC are both poorly absorbed in the intestines and exhibited segment-dependent permeability. The intestinal permeability of CAPB and CAPC were significantly increased by the co-treatment of verapamil, indomethacin. In addition, the intestinal permeability of CAPB was also enhanced by ketoconazole and cyclosporine A. It can be concluded that the intestinal absorption mechanisms of CAPB and CAPC involve processes such as facilitated passive diffusion, efflux transporters, and enzyme-mediated metabolism. Both CAPB and CAPC are suggested to be substrates of P-gp and MRP2. However, CAPB may interact with the CYP3A4 system.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

In Vitro and In Situ Characterization of the Intestinal Absorption of Capilliposide B and Capilliposide C from Lysimachia capillipes Hemsl

Zhang

Cheng

et al. 2019

Molecules

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“…[20][21][22] High ABCB1 expression is usually associated with poor prognosis in cancer patients. 23,24 It affects the absorption, distribution, metabolism, and excretion of drugs [25][26][27] such as the anticancer medicines colchicine, quinidine, tacrolimus, etoposide, doxorubicin, paclitaxel, and vinblastine. 26 The overexpression of ABCB1 in cancer cells increases drug efflux and reduces drug concentrations, thus reducing the cytotoxicity of the drug against tumor cells and resulting in drug resistance.…”

Section: Discussionmentioning

confidence: 99%

The ABCB1 3435C > T polymorphism influences docetaxel transportation in ovarian cancer

et al. 2019

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Objective To investigate the effect of the ATP-binding cassette transporter superfamily B member 1 gene ( ABCB1) 3435C > T single nucleotide polymorphism (SNP) on docetaxel transportation in ovarian cancer cells. Methods ES-2 and SKOV3 cells were transfected with an ABCB1 3435C > T recombinant plasmid, and mRNA expression was detected by real-time PCR. The MTT assay was used to detect the toxicity of docetaxel. High-performance liquid chromatography determined the drug concentration in different cell models to evaluate intracellular accumulation, and a transmembrane resistance experiment was used to assess permeability and evaluate the effect of P-gp activity on drug transportation. A tumor-bearing mouse model was established to evaluate the effect of ABCB1 3435C > T on docetaxel resistance. Results P-gp was overexpressed in cells transfected with the ABCB1 3435C > T plasmid, leading to a significant increase in drug resistance to docetaxel. ABCB1 3435C/wild-type transfection significantly promoted the transport of docetaxel mediated by P-gp compared with ABCB1 3435T/mutant transfection. Conclusion P-gp encoded by the ABCB1 variant allele appears to be more efficient at transporting docetaxel compared with the wild-type allele. The ABCB1 3435C > T SNP dramatically affected the efflux ability of P-gp against docetaxel, and may influence P-gp expression and activity.

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“…Drug metabolism enzymes are critical factors for drug bioavailability. The cytochrome P450 enzyme (CYP450) is one of the crucial hepatic enzymes, responsible for most of the drug metabolism [134]. CYP2D6 is one of the major subtypes of cytochrome P450 [135].…”

Section: Pharmacokinetics and Toxicological Propertiesmentioning

confidence: 99%

Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition

et al. 2021

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Inflammation plays an important role in different chronic diseases. Brominated indoles derived from the Australian marine mollusk Dicathais orbita (D. orbita) are of interest for their anti-inflammatory properties. This study evaluates the binding mechanism and potentiality of several brominated indoles (tyrindoxyl sulfate, tyrindoleninone, 6-bromoisatin, and 6,6′-dibromoindirubin) against inflammatory mediators cyclooxygenases-1/2 (COX-1/2) using molecular docking, followed by molecular dynamics simulation, along with physicochemical, drug-likeness, pharmacokinetic (pk), and toxicokinetic (tk) properties. Molecular docking identified that these indole compounds are anchored, with the main amino acid residues, positioned in the binding pocket of the COX-1/2, required for selective inhibition. Moreover, the molecular dynamics simulation based on root mean square deviation (RMSD), radius of gyration (Rg), solvent accessible surface area (SASA), and root mean square fluctuation (RMSF) analyses showed that these natural brominated molecules transit rapidly to a progressive constant configuration during binding with COX-1/2 and seem to accomplish a consistent dynamic behavior by maintaining conformational stability and compactness. The results were comparable to the Food and Drug Administration (FDA)-approved selective COX inhibitor, aspirin. Furthermore, the free energy of binding for the compounds assessed by molecular mechanics–Poisson–Boltzmann surface area (MM–PBSA) confirmed the binding capacity of indoles towards COX-1/2, with suitable binding energy values except for the polar precursor tyrindoxyl sulfate (with COX-1). The physicochemical and drug-likeness analysis showed zero violations of Lipinski’s rule, and the compounds are predicted to have excellent pharmacokinetic profiles. These indoles are projected to be non-mutagenic and free from hepatotoxicity, with no inhibition of human ether-a-go–go gene (hERG) I inhibitors, and the oral acute toxicity LD50 in rats is predicted to be similar or lower than aspirin. Overall, this work has identified a plausible mechanism for selective COX inhibition by natural marine indoles as potential therapeutic candidates for the mitigation of inflammation.

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Inhibition of P-glycoprotein, multidrug resistance-associated protein 2 and cytochrome P450 3A4 improves the oral absorption of octreotide in rats with portal hypertension

Cited by 5 publications

References 29 publications

In Vitro and In Situ Characterization of the Intestinal Absorption of Capilliposide B and Capilliposide C from Lysimachia capillipes Hemsl

In Vitro and In Situ Characterization of the Intestinal Absorption of Capilliposide B and Capilliposide C from Lysimachia capillipes Hemsl

The ABCB1 3435C > T polymorphism influences docetaxel transportation in ovarian cancer

Mollusc-Derived Brominated Indoles for the Selective Inhibition of Cyclooxygenase: A Computational Expedition

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