Lesser G J, Grossman S A, Eller S, Rowinsky E K
Johns Hopkins Oncology Center, Baltimore, MD 21287, USA.
Cancer Chemother Pharmacol. 1995;37(1-2):173-8. doi: 10.1007/BF00685646.
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 microC/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 microns 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 paclitaxel-induced 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.
