Differences in N-acetylation of the experimental antitumor agent batracylin in the mouse and the rat

M. M. Ames, D. A. Mathiesen, Joel M Reid

Research output: Contribution to journalArticle

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Abstract

Batracylin (NSC 320846) is a quinalzolineone recently evaluated as a potential antitumor agent by the National Cancer Institute. The analog was active against a number of murine tumors, including colon adenocarcinoma 38 and multidrug resistant sublines of P-388 leukemia. Preclinical toxicity studies revealed that batracylin was much more toxic when administered orally to rats than to mice. The combined sex LD10 in mice was 5,655 mg/m2 while 576 mg/m2 was lethal to all rats treated at that dose. We determined that following oral administration of batracylin, systemic exposure of parent drug to the rat was only 14.9% of that to the mouse. It was subsequently noted that systemic exposure of a relatively non-polar metabolite was approximately 9 times greater in the rat than in the mouse. The metabolite was identified as N-acetylbatracylin by TLC, HPLC and mass spectral analyses. Observations by the National Cancer Institute that N-acetylbatracylin was not toxic following oral administration to mice or rats prompted evaluation of systemic exposure following oral administration to rats. Following oral administration of N-acetylbatracylin to rats, systemic exposure was almost nil. Indeed, exposure of rats to N-acetylbatracylin was several orders of magnitude greater following oral administration of six-fold lower doses of the parent drug, batracylin. Thus, N-acetylation may play a role in the toxicity of batracylin despite the lack of toxicity observed following oral administration of N-acetylbatracylin. In addition, further metabolism of the N-acetyl conjugate, analogous to that of other aromataic amines, may be involved in the pharmacology of batracylin and similar analogs.

Original languageEnglish (US)
Pages (from-to)219-225
Number of pages7
JournalInvestigational New Drugs
Volume9
Issue number3
StatePublished - 1991

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batracylin
Acetylation
Antineoplastic Agents
Oral Administration
National Cancer Institute (U.S.)
Poisons
Pharmaceutical Preparations

Keywords

  • batracylin
  • metabolism
  • mice
  • N-acetylation
  • preclinical pharmacology
  • rats

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Differences in N-acetylation of the experimental antitumor agent batracylin in the mouse and the rat. / Ames, M. M.; Mathiesen, D. A.; Reid, Joel M.

In: Investigational New Drugs, Vol. 9, No. 3, 1991, p. 219-225.

Research output: Contribution to journalArticle

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