Absence of Both Cytochrome <i>P</i>450 3A and P-glycoprotein Dramatically Increases Docetaxel Oral Bioavailability and Risk of Intestinal Toxicity

Waterschoot, Robert A.B. van; Lagas, Jurjen S.; Wagenaar, Els; Kruijssen, Cornelia M.M. van der; Herwaarden, Antonius E. van; Song, Ji‐Ying; Rooswinkel, Rogier W.; Tellingen, Olaf van; Rosing, Hilde; Beijnen, Jos H.; Schinkel, Alfred H.

doi:10.1158/0008-5472.can-09-2915

Cited by 87 publications

(120 citation statements)

References 23 publications

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“…1 It acts as a promoter of microtubule polymerization, leading to cell cycle arrest at G2/M, apoptosis, and cytotoxicity. 2,3 An intravenous formulation of docetaxel is currently marketed (Taxotere ® , Sanofi SA, Paris, France).…”

Section: Introductionmentioning

confidence: 99%

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

Cho¹,

Park²,

Yoon³

et al. 2014

IJN

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Docetaxel is a potent anticancer drug, but development of an oral formulation has been hindered mainly due to its poor oral bioavailability. In this study, solid lipid nanoparticles (SLNs) surface-modified by Tween 80 or D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS 1000) were prepared and evaluated in terms of their feasibility as oral delivery systems for docetaxel. Tween 80-emulsified and TPGS 1000-emulsified tristearin-based lipidic nanoparticles were prepared by a solvent-diffusion method, and their particle size distribution, zeta potential, drug loading, and particle morphology were characterized. An in vitro release study showed a sustained-release profile of docetaxel from the SLNs compared with an intravenous docetaxel formulation (Taxotere®). Tween 80-emulsified SLNs showed enhanced intestinal absorption, lymphatic uptake, and relative oral bioavailability of docetaxel compared with Taxotere in rats. These results may be attributable to the absorption-enhancing effects of the tristearin nanoparticle. Moreover, compared with Tween 80-emulsified SLNs, the intestinal absorption and relative oral bioavailability of docetaxel in rats were further improved in TPGS 1000-emulsified SLNs, probably due to better inhibition of drug efflux by TPGS 1000, along with intestinal lymphatic uptake. Taken together, it is worth noting that these surface-modified SLNs may serve as efficient oral delivery systems for docetaxel.

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Section: Introductionmentioning

confidence: 99%

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

Cho¹,

Park²,

Yoon³

et al. 2014

IJN

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“…Interestingly, substrates of both CYP3A4 and P-gp overlap extensively (6). Based on in vivo experiments, researchers have demonstrated that CYP3A and P-gp have possible cooperative functions on drug metabolism and excretion in the liver and small intestine (7,8).…”

Section: Introductionmentioning

confidence: 99%

Downregulation of CYP3A and P-Glycoprotein in the Secondary Inflammatory Response of Mice With Dextran Sulfate Sodium–Induced Colitis and Its Contribution to Cyclosporine A Blood Concentrations

et al. 2014

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Abstract. CYP3A and P-glycoprotein (P-gp) play important roles in drug metabolism and excretion; however, their functions in pathological conditions remain unclear. Hepatobiliary abnormalities have been described in patients with ulcerative colitis, which may affect drug metabolism and excretion in the liver and small intestine. We examined the functions of CYP3A and P-gp in the liver and small intestine of mice with dextran sodium sulfate (DSS)-induced colitis. Up to day 7, inflammatory markers were significantly increased in the livers of DSS-treated mice, accompanied by decreased CYP3A. Additionally hepatobiliary transporters and Pregnane X receptor, which regulates the transcriptional activation of CYP3A, were reduced. Both CYP3A and P-gp were significantly decreased in the upper small intestine of DSS-treated mice on day 7. This was associated with the increased expression of inducible nitric oxide synthase, but not changes in nuclear receptor expression. On day 7 of DSS treatment, the concentrations of cyclosporine A (CsA), a substrate of both CYP3A and P-gp, were significantly higher than controls. These results indicated the existence of a second inflammatory response in the liver and upper small intestine of mice with DSS-induced colitis, and bioavailability of CsA was increased by the dysfunction of CYP3A and P-gp in these organs.[Supplementary Tables and Figure: available only at http://dx

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“…P-gp is one of the most prevalent efflux transporters (Aller et al, 2009;Chen et al, 2011) and plays an important role in limiting the intestinal absorption of many compounds that are its substrates (Kusuhara and Sugiyama, 2002;del Amo et al, 2009). Inhibition of P-gp leads to the improvement of oral bioavailability of several anticancer drugs (Meerum Terwogt et al, 1998;Kemper et al, 2004;van Waterschoot et al, 2009), including ginsenoside Rh2 (Yang et al, 2011). A better understanding of P-gp involvement in the transport of ginsenosides and a more quantitative measurement with regard to if and how P-gp affects their bioavailabilities and potential drug-drug interactions are important for the development of ginsenosides as chemopreventive agents, because these studies are recommended by the Food and Drug Administration in recently published Drug-Drug Interaction Guidance (February, 2012, www.fda.gov).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of P-Glycoprotein Leads to Improved Oral Bioavailability of Compound K, an Anticancer Metabolite of Red Ginseng Extract Produced by Gut Microflora

Yang

Wang²,

Niu³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Ginsenosides are hydrolyzed extensively by gut microflora after oral administration, and their metabolites are pharmacologically active against lung cancer cells. In this study, we measured the metabolism of various ginsenosides by gut microflora and determined the mechanisms responsible for the observed pharmacokinetic behaviors of its active metabolite, Compound K (C-K). The results showed that biotransformation into C-K is the major metabolic pathway of ginsenosides after the oral administration of the red ginseng extract containing both protopanaxadiol and protopanaxatriol ginsenosides. Pharmacokinetic studies in normal mice showed that C-K exhibited low oral bioavailability. To define the mechanisms responsible for this low bioavailability, two P-glycoprotein (P-gp) inhibitors, verapamil and cyclosporine A, were used, and their presence substantially decreased C-K's efflux ratio in Caco-2 cells (from 26.6 to <3) and significantly increased intracellular concentrations (by as much as 40-fold). Similar results were obtained when transcellular transport of C-K was determined using multidrug resistance 1 (MDR1)-overexpressing Madin-Darby canine kidney II cells. In MDR1a/b(؊/؊) FVB mice, its plasma C max and AUC 0-24h were increased substantially by 4.0-and 11.7-fold, respectively. These increases appear to be due to slower elimination and faster absorption of C-K in MDR1a/b(؊/؊) mice. In conclusion, C-K is the major active metabolite of ginsenosides after microflora hydrolysis of primary ginsenosides in the red ginseng extract, and inhibition/deficiency of P-gp can lead to large enhancement of its absorption and bioavailability.

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Absence of Both Cytochrome P450 3A and P-glycoprotein Dramatically Increases Docetaxel Oral Bioavailability and Risk of Intestinal Toxicity

Cited by 87 publications

References 23 publications

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

Downregulation of CYP3A and P-Glycoprotein in the Secondary Inflammatory Response of Mice With Dextran Sulfate Sodium–Induced Colitis and Its Contribution to Cyclosporine A Blood Concentrations

Inhibition of P-Glycoprotein Leads to Improved Oral Bioavailability of Compound K, an Anticancer Metabolite of Red Ginseng Extract Produced by Gut Microflora

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