Pharmacokinetics of paclitaxel and three major metabolites in patients with advanced breast carcinoma refractory to anthracycline therapy treated with a 3-hour paclitaxel infusion: A European Cancer Centre (ECC) trial

M. T. Huizing, J. B. Vermorken, H. Rosing, W. W Ten Bokkel Huinink, I. Mandjes, H. M. Pinedo, J. H. Beijnen

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Hepatic metabolism and biliary clearance play pivotal roles in the disposition of the anticancer drug paclitaxel. 6-α-hydroxypaclitaxel, 3′-p-hydroxypaclitaxel and 6-a,3′-p-dihydroxypaclitaxel were the major metabolic products of paclitaxel found in human bile. Recently, these metabolic products were detected in human plasma. The pharmacokinetics of paclitaxel and its metabolites were investigated in anthracycline-resistant breast cancer patients treated with high-dose paclitaxel and granulocyte colony-stimulating factor (G-CSF) support. Patients and methods: Nine patients were entered into this study in which paclitaxel was administered at the relatively high dose of 250 mg/m2 during a 3-hour infusion. G-CSF was administered daily subcutaneously (s.c.) on days 2 to 19 following chemotherapy. Analysis of paclitaxel and metabolite concentrations was performed by a new highly sensitive reversed-phase high performance liquid chromato-graphic (HPLC) assay. Results: The dose-limiting toxicity in this study was cumulative neurotoxicity. One patient had a partial response and 2 patients had mixed responses of their skin metastases.Relatively low peak plasma concentration (Cmax) with mean values of 6.91 μmol/L (range 3.08 to 8.98) and area under the plasma concentration time curve (AUC), with mean values of 27.04 μmol/L.h (range 14.88 to 40.57), were observed. The total body clearance was 16.99 L/h (range, 10.25 to 27.39). The pharmacokinetic parameter for the prediction of leuko-neutropenia, the duration of the plasma concentration above the threshold of 0.1 μmol/L (T>0.1 μM), was 19.72 h (range 10.54 to 26.31). The three major metabolites detected in human plasma were identified as 6-α-hydroxy-paclitaxel, 3′-p-hydroxypaclitaxel and 6-α,3′-p-dihydroxy-paclitaxel. Cmax and AUC values of these metabolites are reported. Conclusions: The three main metabolic products of paclitaxel in human plasma are 6-α-hydroxypaclitaxel, 3′-p-hydroxypaclitaxel and the dihydroxymetabolite 6-a,3′-p-di-hydroxypaclitaxel. Two patients with liver function disturbances showed a tendency to higher paclitaxel and 6-ct-hydroxypaclitaxel AUC levels, with more pronounced neuropathy.

Original languageEnglish (US)
Pages (from-to)699-704
Number of pages6
JournalAnnals of Oncology
Volume6
Issue number7
StatePublished - Sep 1995
Externally publishedYes

Keywords

  • Anthracycline
  • Breast cancer
  • Hydroxylated metabolites
  • Paclitaxel (Taxol®)
  • Pharmacokinetics
  • Resistance

ASJC Scopus subject areas

  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Public Health, Environmental and Occupational Health
  • Neuropsychology and Physiological Psychology
  • Hematology
  • Oncology
  • Cancer Research

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