Enhanced oral bioavailability of paclitaxel by D-alpha-tocopheryl polyethylene glycol 400 succinate in mice.
Paclitaxel is widely used to treat several types of solid tumors. The commercially available paclitaxel formulation contains Cremophor/ethanol as solubilizers. This study evaluated the effects of D-alpha-tocopheryl polyethylene glycol 400 succinate (TPGS 400) on the oral absorption of paclitaxel in mice. Mice were given an intravenous (18mg/kg) or oral (100mg/kg) dose of paclitaxel solubilized in Cremophor/ethanol or in TPGS 400/ethanol formulations. Paclitaxel plasma concentrations and pharmacokinetic parameters were determined. The maximal plasma concentrations of paclitaxel after an oral dose were 1.77+/-0.17 and 3.39+/-0.49microg/ml for Cremophor/ethanol and TPGS 400/ethanol formulations, respectively, with a similar time at 40-47min to reach the maximal plasma concentrations. The oral bioavailability of paclitaxel in TPGS 400/ethanol (7.8%) was 3-fold higher than that in Cremophor/ethanol (2.5%). On the other hand, the plasma pharmacokinetic profiles of intravenous paclitaxel demonstrated a superimposition for the two formulations. Furthermore, TPGS 400 concentration-dependently increased the intracellular retention of Rhodamine 123 in Caco-2 cells and enhanced paclitaxel permeability in monolayer Caco-2 cultures. TPGS 400 at concentrations up to 1mM did not inhibit testosterone 6beta-hydroxylase, a cytochrome P450 isozyme 3A in liver microsomes metabolizing paclitaxel. Our results indicated that TPGS 400 enhances the oral bioavailability of paclitaxel in mice and the enhancement may result from an increase in intestinal absorption of paclitaxel.
Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli 35053, Taiwan.
Pei-Yin
PY
Ho
Teng-Kuang
TK
Yeh
Hsien-Tsung
HT
Yao
Heng-Liang
HL
Lin
Hsin-Yi
HY
Wu
Yu-Kang
YK
Lo
Yi-Wei
YW
Chang
Tien-Hui
TH
Chiang
Stephen H W
SH
Wu
Yu-Sheng
YS
Chao
Chiung-Tong
CT
Chen
D000284:Administration, Oral; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D018938:Caco-2 Cells; D000431:Ethanol / Q000737:chemistry; D005990:Glycerol / Q000031:analogs & derivatives / Q000737:chemistry; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D017239:Paclitaxel / Q000008:administration & dosage / Q000493:pharmacokinetics*; D010539:Permeability; D011092:Polyethylene Glycols / Q000737:chemistry; D020112:Rhodamine 123 / Q000493:pharmacokinetics; D012997:Solvents / Q000737:chemistry*; D013250:Steroid Hydroxylases / Q000187:drug effects / Q000378:metabolism; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000737:chemistry
D000972:Antineoplastic Agents, Phytogenic; D012997:Solvents; D014810:Vitamin E; D020112:Rhodamine 123; D000431:Ethanol; D011092:Polyethylene Glycols; C000515:cremophor EL; D013250:Steroid Hydroxylases; C022657:steroid hormone 6-beta-hydroxylase; C014225:tocophersolan; D017239:Paclitaxel; D005990:Glycerol