Plasma pharmacokinetics and tissue distribution of paclitaxel in CD2F1 mice

We defined the pharmacokinetics of paclitaxel after i.v., i.p., p.o., and s.c. administration of 22.5 mg/kg to CD2F1 mice. Additional mice were studied after i.v. bolus dosing at 11.25 mg/kg or 3-h continuous i.v. infusions delivered at 43.24 micrograms kg-1 min-1. Plasma was sampled between 5 min and 40 h after dosing. Brains, hearts, lungs, livers, kidneys, skeletal muscles, and, where applicable, testicles were sampled after i.v. dosing at 22.5 mg/kg. Liquid-liquid extraction followed by isocratic high-performance liquid chromatography (HPLC) with UV detection was used to determine paclitaxel concentrations in plasma and tissues. After i.v. administration to male mice, paclitaxel clearance (CLtb) was 3.25 ml min-1 kg-1 and the terminal half-life (t1/2) was 69 min. After i.v. administration to female mice, paclitaxel CLtb was 4.54 ml min-1 kg-1 and the terminal t1/2 was 43 min. The bioavailability of paclitaxel was approximately 10%, 0, and 0 after i.p., p.o., and s.c. administration, respectively. Paclitaxel bioavailability after i.p. administration was the same when the drug was delivered in a small volume to mimic the delivery method used to evaluate in vivo antitumor efficacy or when it was delivered in a large volume to simulate clinical protocols using i.p. regional therapy. Paclitaxel was not detected in the plasma of mice after i.p. delivery of the drug as a suspension in Klucel: Tween 80. Pharmacokinetic parameters were similar after i.v. delivery of paclitaxel at 22.5 and 11.25 mg/kg; however, the CLtb calculated in these studies was much lower than that associated with 3-h continuous i.v. infusions. After i.v. administration, paclitaxel was distributed extensively to all tissues but the brain and testicle. These data are useful in interpreting preclinical efficacy studies of paclitaxel and predicting human pharmacokinetics through scaling techniques.