Cancer Chemotherapy and Pharmacology

, Volume 41, Issue 4, pp 299–306 | Cite as

Quantitation of dolastatin-10 using HPLC/electrospray ionization mass spectrometry: application in a phase I clinical trial

  • D. A. Garteiz
  • T. Madden
  • D. E. Beck
  • W. R. Huie
  • K. T. McManus
  • J. L. Abbruzzese
  • W. Chen
  • R. A. Newman
ORIGINAL ARTICLE

Abstract

A highly sensitive and specific assay for the quantitation of the anticancer agent dolastatin-10 (DOL-10) in human plasma is described. The method was based on the use of electrospray ionization-high-performance liquid chromatography/mass spectrometry (ESP-LC/MS). The analytical procedure involved extraction of plasma samples containing DOL-10 and the internal standard (DOL-15) with n-butyl chloride, which was then evaporated under nitrogen. The residue was dissolved in 50 μl mobile phase and 10 μl was subjected to ESP-LC/MS analysis using a C18 microbore column. A linear gradient using water/acetonitrile was used to keep the retention times of the analytes of interest under 5 min. The method exhibited a linear range from 0.005 to 50 ng/ml with a lower limit of quantitation (LLQ) at 0.005 ng/ml. Absolute recoveries of extracted samples in the 85–90% range were obtained. The method's accuracy (≤5% relative error) and precision (≤10% CV) were well within industry standards. The analytical procedure was applied to extract DOL-10 metabolites from samples obtained following incubation of the drug with an activated S9 rat liver preparation. Two metabolic products were detected and were tentatively identified as a N-demethyl-DOL-10 and hydroxy-DOL-10. Structural assignments were made based on the fragmentation patterns obtained using the electrospray source to produce collision-induced dissociation (CID). The method was also applied to the measurement of DOL-10 in the plasma of patients treated with this drug. Preliminary investigation of the pharmacokinetics suggested that drug distribution and elimination may be best described by a three-compartment model with t1/2α = 0.087 h, t1/2β = 0.69 h and t1/2γ = 8.0 h. Plasma clearance was 3.7 l/h per m2.

Key words Dolastatin-10 Dolastatin-15 Liquid chromatography atmospheric pressure Mass spectrometry Phase I trial 

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Copyright information

© Springer-Verlag Berlin Heidelberg 1998

Authors and Affiliations

  • D. A. Garteiz
    • 3
  • T. Madden
    • 2
  • D. E. Beck
    • 1
  • W. R. Huie
    • 2
  • K. T. McManus
    • 3
  • J. L. Abbruzzese
    • 1
  • W. Chen
    • 1
  • R. A. Newman
    • 1
  1. 1.Department of Clinical Investigation, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USAUS
  2. 2.Department of Experimental Pediatrics, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USAUS
  3. 3.TEXms Inc., 15701 West Hardy Road, Houston, Tx, 77060XX
  4. 4.Clinical Pharmacology Resource Facility, Box 52, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA Tel. +713-792-3608; Fax +713-792-6759US

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