Formulating paclitaxel in nanoparticles alters its disposition.
OBJECTIVE
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 > or = 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.
Yeh
Teng Kuang
TK
College of Pharmacy, The Ohio State University, Columbus, OH, USA.
Lu
Ze
Z
Wientjes
M Guillaume
MG
Au
Jessie L-S
JL
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D000431:Ethanol; D005260:Female; D005780:Gelatin; D007202:Indicators and Reagents; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008863:Microspheres; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols; D012997:Solvents; D014018:Tissue Distribution
D000972:Antineoplastic Agents, Phytogenic; D007202:Indicators and Reagents; D012997:Solvents; C022131:cremophor; D000431:Ethanol; D011092:Polyethylene Glycols; D005780:Gelatin; D017239:Paclitaxel