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Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent

  • Original Article
  • Ansamycins, Antineoplasti Agents, Pharmacokinetic
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Abstract

The plasma pharmacokinetics of the antitumor antibiotic geldanamycin (GM; NSC 122750), a naturally occurring benzoquinoid ansamycin, was characterized in mice and a beagle dog. Concentrations of GM well above 0.1 μg/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 μg/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 drug 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 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). Nevertheless, the drug 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. Drug-related toxicity appeared to be reversible. In consideration of the potential for acute hepatotoxic reactions to GM, 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.

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Abbreviations

GM :

Geldanamycin

IS :

internal standard

GI 50 :

drug concentration for 50% inhibition of cell growth in vitro

LC50 :

drug concentration resulting in 50% lethality in cultured cells

NCI :

National Cancer Institute

AUC :

area under plasma concentrationtime curve between time zero and infinity

CL :

total plasma clearance

MRT :

mean residence time

t 1/2,z :

biological half-life

V 1 :

central compartment apparent volume of distribution

V ss' :

apparent volume of distribution at steady state

V z :

total body apparent volume of distribution

CPK :

creatine phosphokinase

LDH :

lactic dehydrogenase

SGOT :

serum oxaloacetic transaminase

SGPT :

serum glutamic-pyruvic transaminase

DMSO :

dimethyl sulfoxide

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Authors and Affiliations

  1. Laboratory of Pharmaceutical Chemistry, Developmental Therapeutics Program, Division of Cancer Treatment, National Cancer Institute, 21701, Frederick, MD, USA

    Jeffrey G. Supko, Michael R. Grever & Louis Malspeis

  2. Pathology Associates, Inc., 21701, Frederick, MD, USA

    Robert L. Hickman

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  1. Jeffrey G. Supko
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Supko, J.G., Hickman, R.L., Grever, M.R. et al. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother. Pharmacol. 36, 305–315 (1995). https://doi.org/10.1007/BF00689048

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  • DOI: https://doi.org/10.1007/BF00689048

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