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 mic e were studied after i. v. bolus dosing at 11.25 mg/kg or 3-h continuo us i.v. infusions delivered at 43.24 mu g kg(-1) min(-1). Plasma was s ampled between 5 min and 40 h after dosing. Brains, hearts, lungs, liv ers, kidneys, skeletal muscles, and, where applicable, testicles were sampled after i.v. dosing at 22.5 mg/kg. Liquid-liquid extraction foll owed by isocratic high-performance liquid chromatography (HPLC) with U V detection was used to determine paclitaxel concentrations in plasma and tissues. After i.v. administration to male mice, paclitaxel cleara nce (CL(tb)) was 3.25 ml min(-1) kg(-1) and the terminal half-life (t( 1/2)) was 69 min. After i. v. administration to female mice, paclitaxe l CL(tb) was 4.54 ml min(-1) kg(-1) and the terminal t(1/2) was 43 min . The bioavailability of paclitaxel was similar to 10%, 0, and 0 after i. p., p.o., and s.c. administration, respectively. Paclitaxel bioava ilability after i.p. administration was the same when the drug was del ivered 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. Paclitaxe l was not detected in the plasma of mice after i.p. delivery of the dr ug as a sus pension in Klucel:Tween 80. Pharmacokinetic parameters wer e similar after i. v. delivery of paclitaxel at 22.5 and 11.25 mg/kg; however, the CL(tb) calculated in these studies was much lower than th at associated with 3-h continuous i.v. infusions. After i.v. administr ation, paclitaxel was distributed extensively to all tissues but the b rain and testicle. These data are useful in interpreting preclinical e fficacy studies of paclitaxel and predicting human pharmacokinetics th rough scaling techniques.