title: Pharmacokinetics, tissue distribution and anti-tumour efficacy of paclitaxel delivered by polyvinylpyrrolidone solid dispersion.
abstract: OBJECTIVE
  Paclitaxel is a potent anti-cancer drug that has exhibited clinical activity against several tumours. Unfortunately, serious side effects are associated with Taxol, the commercial formulation of paclitaxel, which contains Cremophor EL (CrEL). Currently, the main focus of developing paclitaxel formulations is on improving efficacy and reducing toxicity. A novel, Cremophor-free, paclitaxel solid dispersion (PSD) was prepared in our laboratory previously. The primary aim of this study was to evaluate the pharmacokinetics, tissue distribution, acute toxicity and anti-tumour efficacy of the PSD compared with Taxol.
  
  
  METHODS
  SD rats were used to examine the pharmacokinetics and tissue distribution of PSD. The acute toxicity of PSD was evaluated in ICR mouse. The anti-tumor activity of PSD was assessed in an in vivo anti-tumor nude mice model inoculated with human SKOV-3 cancer cells.
  
  
  RESULTS
  The two formulations presented different pharmacokinetic behaviour. The plasma AUC of paclitaxel in the PSD was 5.84-fold lower than that of Taxol, and the mean residence time, total body clearance and apparent volume of distribution of paclitaxel in the PSD were increased by 1.73, 4.67 and 8.57 fold, respectively. However, the two formulations showed similar tissue distribution properties. CrEL, the vehicle in Taxol, decreased the clearance of paclitaxel from plasma. The LD50 (median lethal dose) was 34.8 mg/kg for Taxol, whereas no death was observed at 160 mg/kg for the PSD. The anti-tumour activity of PSD was similar to that of Taxol at a dose of 15 mg/kg. Most importantly, the improved tolerance of PSD enabled a higher administrable dose of paclitaxel, which resulted in improved efficacy compared with Taxol administered at its maximum tolerated dose.
  
  
  CONCLUSIONS
  These results suggest that the PSD, a CrEL-free formulation, is a promising approach to increase the safety and efficacy of paclitaxel.
authors.affiliation: Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University, Beijing, China.
authors.forename: Xiangrui
authors.initials: X
authors.lastname: Liu
authors.forename: Jiabei
authors.initials: J
authors.lastname: Sun
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Chen
authors.forename: Shanshan
authors.initials: S
authors.lastname: Wang
authors.forename: Hannah
authors.initials: H
authors.lastname: Scott
authors.forename: Xuan
authors.initials: X
authors.lastname: Zhang
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D019540:Area Under Curve; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000493:pharmacokinetics*; D005260:Female; D005990:Glycerol / Q000009:adverse effects / Q000031:analogs & derivatives; D006801:Humans; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D008517:Phytotherapy / Q000379:methods*; D028321:Plant Preparations / Q000493:pharmacokinetics* / Q000494:pharmacology / Q000627:therapeutic use; D011205:Povidone / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020946:Taxus / Q000737:chemistry; D014018:Tissue Distribution
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004337:Drug Carriers; D028321:Plant Preparations; C000515:cremophor EL; D011205:Povidone; D017239:Paclitaxel; D005990:Glycerol