Disposition kinetics of taxanes after intraperitoneal administration in rats and influence of surfactant vehicles

J Pharm Pharmacol. 2004 May;56(5):629-34. doi: 10.1211/0022357023303.

Abstract

Rats were intraperitoneally administered 40 mg x kg(-1) of paclitaxel or docetaxel dissolved in various drug solutions. The drug solutions were prepared using 20 mL of saline, adding 4.2% Cremophor EL (crEL) for paclitaxel (TXL), and 1.5% Polysorbate-80 (PS-80) (TXT), 7.5% PS-80 (TXT+PS-80) or 4.2% crEL (TXT+crEL) for docetaxel. The apparent first-order absorption rate constant from the peritoneal cavity (k(a)) of TXL was about one-twentieth of that of TXT. The ratio of the area under the concentration-time curve of drug in plasma over that in ascites for TXL was about one-third of that of TXT. The values of the above ratio and the k(a) of TXT+PS-80 and TXT+crEL were similar to those of TXL. After intraperitoneal administration, the values of the blood-to-plasma concentration ratio in the four groups were similar and independent of time. In the in-vitro study, PS-80 and crEL caused similar, concentration-dependent decreases of drug permeation into red blood cells after a 15-min incubation of rat blood with 10 microg x mL(-1) of TXL. We demonstrated that the disposition kinetics of taxanes after intraperitoneal administration to rats was strongly influenced, in a concentration-dependent manner, by the surfactant vehicle used, crEL or PS-80.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / administration & dosage
  • Antineoplastic Agents, Phytogenic / pharmacokinetics*
  • Area Under Curve
  • Ascites / metabolism
  • Docetaxel
  • Erythrocytes / metabolism
  • Excipients / chemistry
  • Excipients / pharmacology
  • Female
  • Glycerol / analogs & derivatives*
  • Glycerol / chemistry
  • Glycerol / pharmacology
  • In Vitro Techniques
  • Injections, Intraperitoneal
  • Paclitaxel / administration & dosage
  • Paclitaxel / blood
  • Paclitaxel / pharmacokinetics*
  • Permeability
  • Pharmaceutical Vehicles / chemistry
  • Pharmaceutical Vehicles / pharmacology*
  • Polysorbates / chemistry
  • Polysorbates / pharmacology
  • Rats
  • Surface-Active Agents / chemistry
  • Surface-Active Agents / pharmacology*
  • Taxoids / administration & dosage
  • Taxoids / blood
  • Taxoids / pharmacokinetics*
  • Time Factors
  • Tissue Distribution

Substances

  • Antineoplastic Agents, Phytogenic
  • Excipients
  • Pharmaceutical Vehicles
  • Polysorbates
  • Surface-Active Agents
  • Taxoids
  • Docetaxel
  • cremophor EL
  • Paclitaxel
  • Glycerol