PRECLINICAL PHARMACOLOGICAL EVALUATION OF GELDANAMYCIN AS AN ANTITUMOR AGENT

The plasma pharmacokinetics of the antitumor antibiotic geldanamycin ( GM; NSC 122750), a naturally occurring benzoquinoid ansamycin, was cha racterized in mice and a beagle dog. Concentrations of GM well above 0 .1 mu g/ml, which was typically effective against neoplastic cell line s 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 dura tion of the drug was relatively short. Plasma levels decayed below 0.1 mu g/ml within 3-4 h after administration of the apparent maximum tol erated doses, which were approximately 20 mg/kg for the mice and 4 mg/ kg for the dog. The drug exhibited linear pharmacokinetic behavior wit hin the dose ranges studied. However, there were significant interspec ies differences in its disposition. Whereas the mean biological half-l ife of GM 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). Neverthele ss, the drug was cleared from plasma much faster by the dog (49.4 ml/m in per kg) than by the mice (30.5 ml/min per kg). These apparent anoma lies were principally associated with differences in the relative sign ificance of the terminal phase upon overall drug disposition. The live r 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 cha racteristic of acute hepatic necrosis. Additional effects included sym ptoms of minor gastrointestinal toxicity and alterations in serum chem istry parameters consistent with less severe nephrotoxicity. Drug-rela ted toxicity appeared to be reversible. In consideration of the potent ial for acute hepatotoxic reactions to GM, as well as to the other ben zoquinoid ansamycins based upon structural analogy, additional pharmac ological and therapeutic information is required to ascertain whether these compounds are viable candidates for clinical development.