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Formulating Paclitaxel in Nanoparticles Alters Its Disposition

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Purpose

Paclitaxel is active and widely used to treat multiple types of solid tumors. The commercially available paclitaxel formulation uses Cremophor/ethanol (C/E) as the solubilizers. Other formulations including nanoparticles have been introduced. This study evaluated the effects of nanoparticle formulation of paclitaxel on its tissue distribution.

Methods

We compared the plasma and tissue pharmacokinetics of paclitaxel-loaded gelatin nanoparticles and the C/E formulation. Mice were given paclitaxel-equivalent doses of 10 mg/kg by intravenous injection.

Results

The nanoparticle and C/E formulations showed significant differences in paclitaxel disposition; the nanoparticles yielded 40% smaller area under the blood concentration-time curve and faster blood clearance of total paclitaxel concentrations (sum of free, protein-bound, and nanoparticle-entrapped drug). The two formulations also showed different tissue specificity. The rank order of tissue-to-blood concentration ratios was liver > small intestine > kidney >> large intestine > spleen = stomach > lung > heart for the nanoparticles, and liver > small intestine > large intestine > stomach > lung ≥ kidney > spleen > heart for the C/E formulation. The nanoparticles also showed longer retention and higher accumulation in organs and tissues (average of 3.2 ± 2.3-fold), especially in the liver, small intestine, and kidney. The most striking difference was an 8-fold greater drug accumulation and sustained retention in the kidney.

Conclusions

These data indicate that formulation of paclitaxel affects its clearance and distribution into tissues, with preferential accumulation of nanoparticles in the liver, spleen, small intestine, and kidney.

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Abbreviations

AUC:

area under concentration-time curve

C/E:

Cremophor/ethanol

CL:

clearance

HPLC:

high-performance liquid chromatography

RES:

reticuloendothelial system

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Acknowledgments

This work was supported in part by research grants R37CA49816 and R43CA107743 from the National Cancer Institute, NIH.

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Author notes

  1. Teng Kuang Yeh & Ze Lu

    Present address: Optimum Therapeutics LLC, OSU Science Tech Village, Columbus, Ohio, USA

Authors and Affiliations

  1. College of Pharmacy, The Ohio State University, Columbus, Ohio, USA

    Teng Kuang Yeh, Ze Lu, M. Guillaume Wientjes & Jessie L.-S. Au

  2. James Cancer Hospital and Solove Research Institute, The Ohio State University, Columbus, Ohio, USA

    M. Guillaume Wientjes & Jessie L.-S. Au

Authors
  1. Teng Kuang Yeh
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  2. Ze Lu
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  3. M. Guillaume Wientjes
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  4. Jessie L.-S. Au
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Corresponding author

Correspondence to Jessie L.-S. Au.

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Yeh, T.K., Lu, Z., Wientjes, M.G. et al. Formulating Paclitaxel in Nanoparticles Alters Its Disposition. Pharm Res 22, 867–874 (2005). https://doi.org/10.1007/s11095-005-4581-4

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  • DOI: https://doi.org/10.1007/s11095-005-4581-4

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