Caco-2 permeability, P-glycoprotein transport ratios and brain penetration of heterocyclic drugs

Faassen, Fried; Vogel, G; Spanings, Henry; Vromans, Herman

doi:10.1016/s0378-5173(03)00372-7

Cited by 113 publications

(72 citation statements)

References 35 publications

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“…The permeability/efflux ratios of digoxin with Pgp in several cell lines ranged between 4 and 35 [21,24,102,103]. This contrasts with the permeability/efflux ratios for Pgp at low verapamil concentrations, which were generally lower and ranged from ∼1 to 6 [21,23,24]. These results suggest that the coupling between ATP hydrolysis and transport for drugs may be ligand dependent.…”

Section: Discussionmentioning

confidence: 73%

“…Consistent with the concentrationdependence observed for ATPase activation by verapamil, the drug transport rate is also concentration-dependent. In Caco-2 cells containing human Pgp, verapamil had a higher permeability ratio with Pgp at low opposed to higher verapamil concentrations [23]. Also, human Pgp overexpressed in LLC-PK1 cells had higher efflux ratios at 350 nM than 5 μM verapamil [21,25].…”

Section: Discussionmentioning

confidence: 99%

“…From results of in vitro studies, the drug is known to activate Pgp-coupled ATP-hydrolysis [20]. This drug manifests a spectrum of characteristics, ranging from being a good substrate to a non-substrate for the transporter, which depends on the cell type being evaluated in in vitro cell studies [21][22][23][24][25][26] or host tissue type in in vivo studies [27][28][29]. Although the actual molecular details of these interactions are currently unknown, the drug has been shown to inhibit the ATPase activity of a second drug by competitive, non-competitive and allosteric mechanisms in an in vitro study [30].…”

Section: Introductionmentioning

confidence: 99%

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Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

2016

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SynopsisDrug-drug interactions (DDIs) and associated toxicity from cardiovascular drugs represents a major problem for effective co-administration of cardiovascular therapeutics. A significant amount of drug toxicity from DDIs occurs because of drug interactions and multiple cardiovascular drug binding to the efflux transporter P-glycoprotein (Pgp), which is particularly problematic for cardiovascular drugs because of their relatively low therapeutic indexes. The calcium channel antagonist, verapamil and the cardiac glycoside, digoxin, exhibit DDIs with Pgp through non-competitive inhibition of digoxin transport, which leads to elevated digoxin plasma concentrations and digoxin toxicity. In the present study, verapamil-induced ATPase activation kinetics were biphasic implying at least two verapamil-binding sites on Pgp, whereas monophasic digoxin activation of Pgp-coupled ATPase kinetics suggested a single digoxin-binding site. Using intrinsic protein fluorescence and the saturation transfer double difference (STDD) NMR techniques to probe drug-Pgp interactions, verapamil was found to have little effect on digoxin-Pgp interactions at low concentrations of verapamil, which is consistent with simultaneous binding of the drugs and non-competitive inhibition. Higher concentrations of verapamil caused significant disruption of digoxin-Pgp interactions that suggested overlapping and competing drug-binding sites. These interactions correlated to drug-induced conformational changes deduced from acrylamide quenching of Pgp tryptophan fluorescence. Also, Pgp-coupled ATPase activity kinetics measured with a range of verapamil and digoxin concentrations fit well to a DDI model encompassing non-competitive and competitive inhibition of digoxin by verapamil. The results and previous transport studies were combined into a comprehensive model of verapamil-digoxin DDIs encompassing drug binding, ATP hydrolysis, transport and conformational changes.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

2016

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“…The overexpression of P-gp efflux proteins in Caco-2 cells has been well documented in several literature reports (Faassen et al, 2003;Konsoula and Jung, 2009). In Caco-2 cells, P-gp confers resistance by preventing the absorption of drugs and bioactives through the cells, thereby inhibiting it to reach systemic circulation (Shugarts and Benet, 2009).…”

Section: P-gp Efflux Assaymentioning

confidence: 88%

Enhancing biopharmaceutical attributes of phospholipid complex-loaded nanostructured lipidic carriers of mangiferin: Systematic development, characterization and evaluation

Khurana

Bansal

Beg

et al. 2017

International Journal of Pharmaceutics

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Mangiferin (Mgf), largely expressed out from the leaves and stem bark of Mango, is a potent antioxidant. However, its in vivo activity gets tremendously reduced owing to poor aqueous solubility and inconsistent gastrointestinal absorption, high hepatic first-pass metabolism and high P-gp efflux. The current research work, therefore, was undertaken to overcome the biopharmaceutical hiccups by developing the Mgfphospholipid complex (PLCs) loaded in nanostructured lipidic carriers (NLCs). The PLCs and NLCs were prepared using refluxing, solvent evaporation and hot emulsification technique, respectively with various molar ratios of Mgf and Phospholipon 90 G, i.e., 1:1; 1:2; and 1:3. The complex was evaluated for various physicochemical parameters like drug content (96.57%), aqueous solubility (25-fold improved) and oil-water partition coefficient (10-fold enhanced). Diverse studies on the prepared complex using FTIR, DSC, PXRD and SEM studies ratified the formation of PLCs at 1:1 ratio. The PLCs were further incorporated onto NLCs, which were systematically optimized employing a face centered cubic design (FCCD), while evaluating for particle size, zeta potential, encapsulation efficiency and in vitro drug release as the CQAs. Caco-2 cell line indicated insignificant cytotoxicity, and P-gp efflux, bi-directional permeability model and in situ perfusion studies specified enhanced intestinal permeation parameters. In vivo pharmacokinetic studies revealed notable increase in the values of Cmax (4.7-fold) and AUC (2.1-fold), respectively, from PLCs-loaded NLCs vis-à-vis Mgf solution. In a nutshell, the promising results observed from the present research work signified boosted biopharmaceutical potential of the optimized PLCs-loaded NLCs for potentially augmenting the therapeutic efficacy of Mgf.

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“…The PEGylation of the 6-α-hydroxyl side chain of naloxone confers increased oral bioavailability and peripheral selectivity to the naloxone moiety by a reduction in passive permeability across the blood-brain barrier [35]. It is also a substrate of the P-glycoprotein (PGP) transporter, which promotes efflux of naloxegol and serves to further restrict its entry into the central nervous system, [36] thus not affecting the analgesic mechanism of opioids in the central nervous system. It shows strong selectivity (more than 6000 folds) toward peripheral μ receptors.…”

Section: Fig 3: Structure Of Naloxegolmentioning

confidence: 99%

Mu-Opioid Receptor Antagonists and Their Role in Treatment of Chronic Constipation

2017

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Constipation disproportionately affects older adults, with a prevalence of 50% in community-dwelling elderly and 74% in nursing-home residents. Loss of mobility, medications, underlying diseases, impaired anorectic sensation, and ignoring calls to defecate are as important as dyssynergic defecation or irritable bowel syndrome in causing constipation. Opioid antagonists not only have well-established indications in the reversal of lifethreatening opioid toxicity but also hold considerable promise for other applications in palliative care practice, particularly management of opioidinduced constipation (OIC). This review summarizes the pharmacology of new peripherally acting mu (µ) opioid receptor antagonists (PAMORA).

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Caco-2 permeability, P-glycoprotein transport ratios and brain penetration of heterocyclic drugs

Cited by 113 publications

References 35 publications

Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

Unravelling the complex drug–drug interactions of the cardiovascular drugs, verapamil and digoxin, with P-glycoprotein

Enhancing biopharmaceutical attributes of phospholipid complex-loaded nanostructured lipidic carriers of mangiferin: Systematic development, characterization and evaluation

Mu-Opioid Receptor Antagonists and Their Role in Treatment of Chronic Constipation

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