title: High-performance liquid chromatographic assay for the measurement of the novel microtubule inhibitor 1069C85 in biological tissues and fluids.
abstract: 1069C85 is a novel tubulin binder developed to circumvent the resistance associated with the Vinca alkaloids. Cytotoxic activity has been demonstrated in vitro against a variety of tumour cell lines, including a variant of the P388 leukaemia with acquired resistance to vincristine. A phase I clinical trial is planned and an assay suitable for preclinical and clinical pharmacokinetics has been developed. A high-performance liquid chromatographic (HPLC) assay is described which allows measurement of 1069C85 in plasma, urine, and tissue samples. The method uses reversed-phase chromatography with isocratic elution and detection by fluorescence at 406 nm following excitation at 340 nm. The assay is specific, sensitive (limit of sensitivity 0.25 ng/ml) and reproducible (coefficient of variation < 5%). The method has been used to study the pharmacokinetics of 1069C85 in Balb C mice following a single oral dose of 1 mg/kg. The maximum plasma concentration was reached 15 min after administration and subsequent elimination was slow with a half life of 6.5 +/- 2.2 h. The drug remained detectable in plasma, at 1 +/- 0.5 ng/ml, 24 h after this dose. This assay will be used to determine the pharmacokinetic profile of 1069C85 in mice and in a forthcoming phase I clinical trial.
authors.affiliation: Drug Development Section, Institute of Cancer Research, Belmont, Sutton, Surrey, UK.
authors.forename: F
authors.initials: F
authors.lastname: Raynaud
authors.forename: M
authors.initials: M
authors.lastname: Walton
authors.forename: I
authors.initials: I
authors.lastname: Judson
mesh_terms: D000818:Animals; D001682:Biological Availability; D002219:Carbamates / Q000032:analysis* / Q000737:chemistry / Q000493:pharmacokinetics; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006207:Half-Life; D006801:Humans; D007408:Intestinal Absorption; D051379:Mice; D008807:Mice, Inbred BALB C; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism*; D011724:Pyridazines / Q000032:analysis* / Q000737:chemistry / Q000493:pharmacokinetics; D012995:Solubility; D012997:Solvents; D013050:Spectrometry, Fluorescence
chemical_list: C086346:BW 1069C85; D002219:Carbamates; D011724:Pyridazines; D012997:Solvents