Preclinical pharmacology of 1069C85, a novel tubulin binder

Cancer Chemother Pharmacol. 1994;35(2):169-73. doi: 10.1007/BF00686642.

Abstract

The compound 1069C85, methyl N-[6-(3,4,5-trimethoxybenzyloxy)imidazo(1,2b)-pyridazin-2-yl ] carbamate, is a novel synthetic tubulin binder currently undergoing phase I clinical trial. It was developed with a view to overcoming multidrug resistance and is given orally. Cytotoxicity studies in vitro against human ovarian carcinoma cell lines showed a lack of cross-resistance with cisplatin and no cross-resistance in two doxorubicin-resistant cell lines that exhibit high levels of resistance to both paclitaxel and vinblastine. Pharmacokinetic studies in BALB/c mice showed the oral bioavailability to be 20%, with 35% of the drug being excreted unchanged in the faeces over the first 24 h. Maximal plasma concentrations (Cmax) were achieved within 2 h of oral administration as compared with 7.5 min following i.v. injection. At a dose of 20 mg/kg, the tumour drug concentration exceeded the plasma Cmax by a factor of 1.5 and was within the in vitro cytotoxic concentration range. The drug showed a linear relationship between the dose and the area under the plasma concentration versus time curve (AUC) for doses of up to 20 mg/kg, above which no further increase in AUC was observed, possibly due to saturable absorption. 1069C85 is highly protein-bound (85%-99%) and appears to be subject to metabolism. The demonstration of cytotoxic activity against multidrug-resistant human tumour cell lines and the detection of potentially cytotoxic levels in an experimental tumour following oral administration support the choice of 1069C85 for clinical development.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / blood
  • Antineoplastic Agents / pharmacokinetics*
  • Antineoplastic Agents / therapeutic use*
  • Biological Availability
  • Carbamates / blood
  • Carbamates / pharmacokinetics*
  • Carbamates / therapeutic use*
  • Chromatography, High Pressure Liquid
  • Doxorubicin / therapeutic use
  • Female
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Neoplasms, Experimental / drug therapy*
  • Paclitaxel / therapeutic use
  • Pyridazines / blood
  • Pyridazines / pharmacokinetics*
  • Pyridazines / therapeutic use*
  • Tissue Distribution
  • Tubulin / metabolism*
  • Tumor Cells, Cultured / drug effects
  • Vinblastine / therapeutic use

Substances

  • Antineoplastic Agents
  • BW 1069C85
  • Carbamates
  • Pyridazines
  • Tubulin
  • Vinblastine
  • Doxorubicin
  • Paclitaxel