14 Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent

Supko JG, Hickman RL, Grever MR, Malspeis L

Laboratory of Pharmaceutical Chemistry, National Cancer Institute, Frederick, MD 21701, USA.

The plasma pharmacokinetics of the anti-tumor antibiotic geldanamycin , a naturally occurring benzoquinoid ansamycin, was characterized in mice and a beagle dog. Concentrations of geldanamycin well above 0.1 microgram/ml, which was typically effective against neoplastic cell lines responsive to the drug in vitro, were achieved in the plasma of the mice and the dog treated by i.v. injection. However, the systemic duration of the drug was relatively short. Plasma levels decayed below 0.1 microgram/ml within 3-4 h after administration of the apparent maximum tolerated doses, which were approximately 20 mg/kg for the mice and 4 mg/kg for the dog. The geldanamycin exhibited linear pharmacokinetic behavior within the dose ranges studied. However, there were significant interspecies differences in its disposition. Whereas the mean biological half-life of geldanamycin was slightly longer in the mice (77.7 min) than in the dog (57.9 min), its mean residence time in the dog (46.6 min) was more than twofold greater than that observed in the mice (20.7 min). Nevertheless, the geldanamycin was cleared from plasma much faster by the dog (49.4 ml/min per kg) than by the mice (30.5 ml/min per kg). These apparent anomalies were principally associated with differences in the relative significance of the terminal phase upon overall drug disposition. The liver appeared to be the principal target organ of acute drug toxicity in the dog. Doses of 2.0 and 4.2 mg/kg both produced elevations in serum levels of the transaminases and other indicators of liver function characteristic of acute hepatic necrosis. Additional effects included symptoms of minor gastrointestinal toxicity and alterations in serum chemistry parameters consistent with less severe nephrotoxicity. geldanamycin -related toxicity appeared to be reversible. In consideration of the potential for acute hepatotoxic reactions to geldanamycin , as well as to the other benzoquinoid ansamycins based upon structural analogy, additional pharmacological and therapeutic information is required to ascertain whether these compounds are viable candidates for clinical development.