The distribution of systemically administered [3H]-paclitaxel in rats: a quantitative autoradiographic study

Paclitaxel is an important agent in the treatment of many common malignancies. Although the symptomatic peripheral neuropathy caused by this drug is its principal nonhematologic toxicity, little is known about the distribution of paclitaxel within the peripheral or central nervous system following systemic administration. In order to study paclitaxel's distribution in neural and extraneural tissues, adult Sprague-Dawley rats were sacrificed 2 h after a tail vein injection of ³H]-paclitaxel (0.03 mg/kg, 250 Ci/rat). Samples of lung, heart, liver, spleen, kidney, skeletal muscle, brain, spinal cord, dorsal root ganglion, and peripheral nerve were then removed and snap-frozen. These tissues were sectioned at 10 m in a cryostat and exposed to autoradiography film for 2 weeks. The distribution and concentrations of ³H]-paclitaxel in plasma, urine and cerebrospinal fluid were also determined using liquid scintillation spectrometry. ³H]-Paclitaxel concentrations (and organ/plasma concentration ratios) in plasma, urine and cerebrospinal fluid were 2.6 nM (1), 38 nM (15) and 0.7 nM (0.3), respectively. A relatively homogeneous distribution of ³H]-paclitaxel was observed in liver 412 nM (151)], spleen 351 nM (133)], heart 319 nM (117)], lung 268 nM (93)] and muscle 69 nM (26)]. Higher concentrations of ³H]-paclitaxel were noted in the portal triads 869 nM (361)], glomeruli 797 nM (304)], and renal medulla 961 nM (363)], which may reflect biliary excretion and glomerular filtration. A high concentration of ³H]-paclitaxel was also noted in the choroid plexus 432 nM (167)], but ³H]-paclitaxel was not detected in the brain parenchyma, spinal cord, dorsal root ganglion, peripheral nerve, or the testicles. The pathogenesis of paclitaxelinduced neurotoxicity remains obscure given its limited distribution in the nervous system. In addition, these results suggest that systemically administered paclitaxel is not likely to be effective for the treatment of malignancies in the testes or the nervous system.