Enhanced Oral Absorption of Paclitaxel in a Novel Self-Microemulsifying Drug Delivery System with or Without Concomitant Use of P-Glycoprotein Inhibitors

Yang, Shicheng; Gürsoy, R. Neslihan; Lambert, Grégory; Benita, Simon

doi:10.1023/b:pham.0000016238.44452.f1

Cited by 145 publications

(92 citation statements)

References 27 publications

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“…Other P-glycoprotein blockers that could also serve as CYP 450 inhibitors also boosted the oral absorption of paclitaxel Bardelmeijer et al, 2004;Choi & Li, 2005;Kim et al, 2004;. Formulations that do not contain Cremophor EL, that could lower the in vivo toxicity and increase solubilization of paclitaxel, were shown to deliver paclitaxel efficiently via oral administration especially when P-glycoprotein inhibitors were given simultaneously Gao et al, 2003;Yang et al, 2004;Woo et al, 2003;Choi et al, 2004aChoi et al, , 2004bPeltier et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Development, Optimization and Absorption Mechanism of DHP107, Oral Paclitaxel Formulation for Single-Agent Anticancer Therapy

Lee¹,

Hong²,

Jang³

et al. 2012

New Advances in the Basic and Clinical Gastroenterology

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Section: Introductionmentioning

confidence: 99%

Development, Optimization and Absorption Mechanism of DHP107, Oral Paclitaxel Formulation for Single-Agent Anticancer Therapy

Lee¹,

Hong²,

Jang³

et al. 2012

New Advances in the Basic and Clinical Gastroenterology

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“…2) Un tel profil a été décrit auparavant dans la littérature [24,36]. La demi-vie d'élimination du principe actif est de 4,5 h et le TRM de 2,6 h. Ces deux résultats concordent aussi avec des valeurs antérieurement décrites [16,22,23]. Quand le médicament commercial est administré par voie orale, les niveaux plasmatiques du paclitaxel sont inférieurs à la limite de détection de la technique analytique utilisée.…”

Section: Discussion Et Conclusionunclassified

“…Pour résoudre ce problème tout en promouvant la biodisponibilité orale du paclitaxel, le recours à plusieurs systèmes de délivrance de médicaments a été envisagé : micelles [21], systèmes autoemulsionables [22,23], nanoémulsions [24] et nanocapsules lipidiques [16]. De tels systèmes permettent, en général, l'association, à la formulation, d'inhibiteurs de la P-gp et du cytochrome P450, tels que la cyclosporine A [22] ou des flavonoïdes [25]. Le présent travail est consacré à la mise au point d'un système permettant l'administration du paclitaxel par voie orale.…”

Section: Introductionunclassified

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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“…Lipid formulations, such as self-microemulsifying drug delivery systems (SMEDDS) (Yang et al, 2004;Lo et al, 2010;Oostendorp et al, 2011) and lipid nanocapsules (LNC) (Peltier et al, 2006) have been reported to enhance the oral bioavailability of PTX. SMEDDS and LNC formulations of PTX have shown 2-fold and 3-fold higher oral bioavailability, respectively, compared to that of an orally administered Taxol formulation (Yang et al, 2004;Peltier et al, 2006). Mechanisms by which lipids improve the bioavailability of PTX may include enhanced solubilization of PTX in the gastrointestinal lumen and increased absorption via selective lymphatic uptake (Yang et al, 2004;Porter & et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

“…SMEDDS and LNC formulations of PTX have shown 2-fold and 3-fold higher oral bioavailability, respectively, compared to that of an orally administered Taxol formulation (Yang et al, 2004;Peltier et al, 2006). Mechanisms by which lipids improve the bioavailability of PTX may include enhanced solubilization of PTX in the gastrointestinal lumen and increased absorption via selective lymphatic uptake (Yang et al, 2004;Porter & et al, 2007). Lipidbased formulations have been widely applied for highly lipophilic drugs to promote their intestinal lymphatic transport (Ling et al, 2006;Murota et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Effects of lipid vehicle and P-glycoprotein inhibition on the mesenteric lymphatic transport of paclitaxel in unconscious, lymph duct-cannulated rats

Cai

Deng

et al. 2014

Drug Delivery

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The present study examined the effects of lipid vehicle and intestinally based efflux processes on intestinal lymphatic transport of paclitaxel (PTX) in the mesenteric lymph duct-cannulated anesthetized rat model. PTX solution alone, PTX solution pretreated with the P-glycoprotein (P-gp) inhibitor verapamil and/or PTX and a 2:1 (w/w) mixture of linoleic acid:glycerol monooleate were administered intraduodenally to anesthetized rats. Coadministration of a mixture of linoleic acid-monoolein significantly increased the extent of intestinal lymphatic transport of PTX, but it had little impact on the absolute oral bioavailability of PTX. In contrast, pretreatment with verapamil increased both the extent of lymphatic transport (3.5-fold) and absolute oral bioavailability (1.8-fold). Further increase in the lymphatic transport (6.5-fold) and absolute oral bioavailability (1.8-fold) was achieved by the combination of pretreatment with verapamil and coadministration with the linoleic acid-monoolein mixture. These data indicate that the application of lipid vehicle holds promise for selectively targeted lymphatic delivery of PTX. P-gp inhibition can result in both increased intestinal lymphatic levels and absolute oral bioavailability of PTX.

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Enhanced Oral Absorption of Paclitaxel in a Novel Self-Microemulsifying Drug Delivery System with or Without Concomitant Use of P-Glycoprotein Inhibitors

Abstract: The results indicate that SMEDDS is a promising novel formulation to enhance the oral bioavailability of paclitaxel, especially when coadministered with a suitable P-gp inhibitor, such as CsA.

Cited by 145 publications

References 27 publications

Development, Optimization and Absorption Mechanism of DHP107, Oral Paclitaxel Formulation for Single-Agent Anticancer Therapy

Development, Optimization and Absorption Mechanism of DHP107, Oral Paclitaxel Formulation for Single-Agent Anticancer Therapy

Nanoparticules mucopénétrantes : véhicules pour l’administration orale du paclitaxel

Effects of lipid vehicle and P-glycoprotein inhibition on the mesenteric lymphatic transport of paclitaxel in unconscious, lymph duct-cannulated rats

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