Differences in N-acetylation of the experimental antitumor agent batracylin in the mouse and the rat.
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 aromatic amines, may be involved in the pharmacology of batracylin and similar analogs.
Ames
M M
MM
Mayo Clinic and Foundation, Department of Oncology, Rochester, MN 55905.
Mathiesen
D A
DA
Reid
J M
JM
D000107:Acetylation; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D007928:Lethal Dose 50; D051379:Mice; D011799:Quinazolines / Q000378:metabolism* / Q000493:pharmacokinetics / Q000633:toxicity; D051381:Rats; D013045:Species Specificity
D000970:Antineoplastic Agents; D011799:Quinazolines; C057924:batracylin