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

Glenn J. Lesser, Stuart A. Grossman, Susan Eller, Eric K. Rowinsky

Research output: Contribution to journalArticlepeer-review

Abstract

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 μCi/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 μm 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 n M (1), 38 n M (15) and 0.7 n M (0.3), respectively. A relatively homogeneous distribution of [3H]-paclitaxel was observed in liver [412 n M (151)], spleen [351 n M (133)], heart [319 n M (117)], lung [268 n M (93)] and muscle [69 n M (26)]. Higher concentrations of [3H]-paclitaxel were noted in the portal triads [869 n M (361)], glomeruli [797 n M (304)], and renal medulla [961 n M (363)], which may reflect biliary excretion and glomerular filtration. A high concentration of [3H]-paclitaxel was also noted in the choroid plexus [432 n M (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.

Original languageEnglish (US)
Pages (from-to)173-178
Number of pages6
JournalCancer Chemotherapy and Pharmacology
Volume37
Issue number1-2
DOIs
StatePublished - Jan 1 1995

Keywords

  • Paclitaxel
  • Peripheral neuropathy
  • Tissue distribution

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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