Preclinical pharmacology of 1069C85, a novel tubulin binder.
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.
Raynaud
F I
FI
Drug Development Section, Institute of Cancer Research, Sutton, Surey, UK.
Kelland
L R
LR
Walton
M I
MI
Judson
I R
IR
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001682:Biological Availability; D002219:Carbamates / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D002851:Chromatography, High Pressure Liquid; D004317:Doxorubicin / Q000627:therapeutic use; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000188:drug therapy*; D017239:Paclitaxel / Q000627:therapeutic use; D011724:Pyridazines / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014018:Tissue Distribution; D014404:Tubulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014747:Vinblastine / Q000627:therapeutic use
D000970:Antineoplastic Agents; C086346:BW 1069C85; D002219:Carbamates; D011724:Pyridazines; D014404:Tubulin; D014747:Vinblastine; D004317:Doxorubicin; D017239:Paclitaxel