The ATP-Binding Cassette Transporters and Their Implication in Drug Disposition: A Special Look at the Heart

Couture, Lucie; Nash, John A.; Turgeon, Jacques

doi:10.1124/pr.58.2.7

Cited by 99 publications

(96 citation statements)

References 146 publications

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“…Additionally, it is known that the hepatic extraction of free bile acids is also less efficient compared with the conjugated forms (35), and this further explains the greater proportion of unconjugated bile acids in the systemic circulation and consequently, the kidney and heart. At physiological pH, conjugated bile acids are negatively charged and require carrier-mediated transport across tissue membranes; therefore, it is likely that these organspecific profiles arise from selective uptake caused by differential expression of bile acid transporters in the renal tubular cells and cardiomyocytes (28)(29)(30)(31)(32). In a previous study, Dupont et al (36) showed organ-specific differences in the ratios of glycine-and taurine-conjugated bile acids in a range of tissues from miniature swine using gas liquid chromatography.…”

Section: Discussionmentioning

confidence: 99%

“…Although the biological significance of bile acids in the heart remains to be elucidated, given their known function as signaling molecules and the presence of the FXR and TGR5 receptors in addition to bile acid transporters in the heart (26,27,31,32), it is feasible that bile acids serve a regulatory role in cardiomyocyte metabolism. A minor route of bile acid elimination is urinary excretion, removing excess bile acids from systemic circulation.…”

Section: Discussionmentioning

confidence: 99%

“…The global signaling capacity of bile acids is currently unclear; however, the expression of bile acid receptors FXR and TGR5 in tissues outside of the enterohepatic circulation, including the kidney (25) and heart (26,27), suggests a greater role throughout the body. Expression of bile acid transporters in renal tubular cells [Asbt (28), organic anion transporting polypeptide 1 (OATP1) (29), and kidney specific organic anion transporter (OATK2) (30)] and cardiomyocytes (31,32) further supports this proposition. Moreover, the involvement of bile acids in the regulation of glucose homeostasis is consistent with the expression of FXR in pancreatic β-cells, which has been shown to play an essential role in the regulation of insulin transcription and secretion induced by glucose (33).…”

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Systemic gut microbial modulation of bile acid metabolism in host tissue compartments

Swann

Want

Geier

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

651

476

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We elucidate the detailed effects of gut microbial depletion on the bile acid sub-metabolome of multiple body compartments (liver, kidney, heart, and blood plasma) in rats. We use a targeted ultraperformance liquid chromatography with time of flight mass-spectrometry assay to characterize the differential primary and secondary bile acid profiles in each tissue and show a major increase in the proportion of taurine-conjugated bile acids in germ-free (GF) and antibiotic (streptomycin/penicillin)-treated rats. Although conjugated bile acids dominate the hepatic profile (97.0 ± 1.5%) of conventional animals, unconjugated bile acids comprise the largest proportion of the total measured bile acid profile in kidney (60.0 ± 10.4%) and heart (53.0 ± 18.5%) tissues. In contrast, in the GF animal, taurine-conjugated bile acids (especially taurocholic acid and tauro-β-muricholic acid) dominated the bile acid profiles (liver: 96.0 ± 14.5%; kidney: 96 ± 1%; heart: 93 ± 1%; plasma: 93.0 ± 2.3%), with unconjugated and glycine-conjugated species representing a small proportion of the profile. Higher free taurine levels were found in GF livers compared with the conventional liver (5.1-fold; P < 0.001). Bile acid diversity was also lower in GF and antibiotic-treated tissues compared with conventional animals. Because bile acids perform important signaling functions, it is clear that these chemical communication networks are strongly influenced by microbial activities or modulation, as evidenced by farnesoid X receptor-regulated pathway transcripts. The presence of specific microbial bile acid co-metabolite patterns in peripheral tissues (including heart and kidney) implies a broader signaling role for these compounds and emphasizes the extent of symbiotic microbial influences in mammalian homeostasis.farnesoid X receptor | gut microbiota | TGR5 | ultra-performance liquid chromatography mass spectrometry | G protein-coupled bile acid receptor 1 T he importance of gut microbiome variation in relation to human health and diverse diseases is now well-recognized (1-4). The microbiome is a virtual organ that performs many digestive and metabolic functions for the host, including enhanced calorific recovery from ingested foods and degradation of complex plant polysaccharides. Microbial communities have coevolved with man and show remarkable diversity dependent on topographical location and interperson variability (5). Co-evolution has refined the microbiome of organisms to a state where metabolic complementarity exists within the microbiota (6), and important biosynthetic/ metabolic pathways are provided for the host that significantly extend host metabolic capacity (3). As such, the mammalian host can be considered a superorganism (7), whose metabolism is the sum of that of both the host and the collective microbial community. The enterohepatic circulation provides a vehicle for this transgenomic metabolism, and bile acids, whose functional role in the global mammalian system is multifaceted, are an important class of metabolites that u...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 85%

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Systemic gut microbial modulation of bile acid metabolism in host tissue compartments

Swann

Want

Geier

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

651

476

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“…Pour toutes ces raisons, nous avons pensé que le recours à ces vecteurs colloïdaux pouvait permettre l'administration orale du paclitaxel en favorisant son cheminement, à travers la couche de mucus intestinal, jusqu'à la surface des entérocytes [33] et en inhibant, à ce niveau, les systèmes à la base de son métabolisme présystémique. A noter qu'au cours de ce travail, la pharmacocinétique et l'efficacité du paclitaxel après incorporation dans des nanoparticules pégylées ont été évalués chez des souris femelles C57BL/6J possèdant le gêne mdr1a codant pour la P-gp intestinale [34]. Les résultats décrits dans ce travail montrent que les nanoparticules avec enrobage de poly (éthylène glycol) ont une taille d'environ 180 nm, une charge superficielle négative.et un contenu en paclitaxel d'environ 150 mg par mg de nanoparticules.…”

Section: Discussion Et Conclusionunclassified

Nanoparticules mucopénétrantes : véhicules pour l’administration orale du paclitaxel

Zabaleta

Calleja

Espuelas

et al. 2013

Annales Pharmaceutiques Françaises

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RésuméLe paclitaxel est un agent anticancéreux utilisé en solution pour perfusion intraveineuse dans le traitement de différents types de cancer. Dans les dernières années, de nombreuses stratégies ont été proposées pour le développement d'une formulation orale de cet anticancéreux. Toutefois, la faible solubilité aqueuse du paclitaxel et le fait qu'il soit un substrat de la pglycoprotéine intestinale et du complexe enzymatique cytochrome P450 compliquent énormément le problème. Dans ce travail, des nanoparticules pégylées avec des propriétés mucopénétrantes ont été développées pour acheminer le paclitaxel jusqu'à la surface des entérocytes. Des particules présentant une taille moyenne d'environ 180 nm et un contenu en paclitaxel proche de 15% ont été préparées. Une étude pharmacocinétique chez la souris a montré que les nanoparticules permettent d'obtenir des niveaux plasmatiques efficaces et soutenus du paclitaxel pendant 3 jours. Au total, la biodisponibilité relative orale du paclitaxel, encapsulé dans des nanoparticules pégylées avec du PEG 2000, est proche du 85%. Chez la souris, sur un modèle de tumeur sous-cutanée, ces mêmes nanoparticules administrées par voie orale, une fois tous les trois jours, ont permis d'obtenir une efficacité similaire à celle offerte par le médicament commercialisé administré par voie intraveineuse journellement pendant 9 jours. L'ensemble des résultats tend à démontrer que les nanoparticules développées sont capables de traverser la couche du mucus intestinal et d'atteindre, ainsi, la surface des entérocytes. Les molécules de PEG favorisent l'adhésion des particules à la surface des cellules, évitent la métabolisation du paclitaxel et accroissent son absorption. Mots-clés : nanoparticules, paclitaxel, orale, poly (éthylène glycol), libération contrôlée SummaryPaclitaxel is an anticancer drug used as solution for perfusion for the treatment of certain types of cancers. In the last years, a number of strategies have been proposed for the development of an oral formulation of this drug. However, this task is quite complicated due to the poor aqueous solubility of paclitaxel as well as the fact that this compound is substrate of the intestinal P-glycoprotein and the cytochrome P450 enzymatic complex. In this work, we have developed pegylated nanoparticles with muco-penetrating properties in order to conduct paclitaxel till the surface of the enterocyte. These nanoparticles displayed a size of about 180 nm and a drug loading close to 15% by weight. The pharmacokinetic study in mice has shown that these nanoparticles were capable to offer therapeutic plasma levels of paclitaxel up to 72 hours. In addition, the oral relative bioavailability of paclitaxel when loaded in nanoparticles pegylated with poly(ethylene glycol) 2000 (PEG) was found to be 85%. In a subcutaneous model of tumour in mice, these pegylated nanoparticles administered orally every 3 days have demonstrated a similar efficacy than Taxol administered intravenously every day during 9 days. 3All of these results suggested ...

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“…Recently, it has been shown that MRP1 is the main transporter protein that effluxes oxidized glutathione from endothelial aorta (42), thus supporting the role of MRP1 in modulating oxidative stress in the cardiovascular system. Several ABC transport mRNA/proteins have been reported to be present in heart to various degrees (43).…”

Section: Discussionmentioning

confidence: 99%

Increase in Mrp1 expression and 4-hydroxy-2-nonenal adduction in heart tissue of Adriamycin-treated C57BL/6 mice

Jungsuwadee¹,

Cole²,

Sultana

et al. 2006

Molecular Cancer Therapeutics

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Multidrug resistance-associated protein 1 (MRP1) mediates the ATP-dependent efflux of endobiotics and xenobiotics, including estradiol 17-(B-D-glucuronide), leukotriene C 4 , and the reduced glutathione conjugate of 4-hydroxy-2-nonenal (HNE), a highly reactive product of lipid peroxidation. Adriamycin is an effective cancer chemotherapeutic drug whose use is limited by cardiotoxicity. Adriamycin induces oxidative stress and production of HNE in cardiac tissue, which may contribute to cardiomyopathy. We investigated the role of Mrp1 in Adriamycin-induced oxidative stress in cardiac tissue. Mice were treated with Adriamycin (20 mg/kg, i.p.), and heart homogenate and sarcolemma membranes were assayed for Mrp1 expression and ATP-dependent transport activity. Expression of Mrp1 was increased at 6 and 24 hours after Adriamycin treatment compared with saline treatment. HNE-adducted proteins were significantly increased (P < 0.001) in the homogenates at 6 hours after Adriamycin treatment and accumulated further with time; HNE adduction of a 190-kDa protein was evident 3 days after Adriamycin treatment. Mrp1 was localized predominately in sarcolemma as shown by confocal and Western blot analysis. Sarcolemma membrane vesicles transported leukotriene C 4 with a K m and V max of 51.8 nmol/L and 94.1 pmol/min/mg, respectively, and MK571 (10 Mmol/L) inhibited the transport activity by 65%.Exposure of HEK Mrp1 membranes to HNE (10 Mmol/L) significantly decreased the V max for estradiol 17-(B-Dglucuronide) transport by 50%. These results show that expression of Mrp1 in the mouse heart is localized predominantly in sarcolemma. Adriamycin treatment increased Mrp1 expression and HNE adduction of Mrp1. Cardiac Mrp1 may play a role in protecting the heart from Adriamycin-induced cardiomyopathy by effluxing HNE conjugates.

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The ATP-Binding Cassette Transporters and Their Implication in Drug Disposition: A Special Look at the Heart

Cited by 99 publications

References 146 publications

Systemic gut microbial modulation of bile acid metabolism in host tissue compartments

Systemic gut microbial modulation of bile acid metabolism in host tissue compartments

Nanoparticules mucopénétrantes : véhicules pour l’administration orale du paclitaxel

Increase in Mrp1 expression and 4-hydroxy-2-nonenal adduction in heart tissue of Adriamycin-treated C57BL/6 mice

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