HUMAN AUTOPSY-TISSUE DISTRIBUTION OF MENOGARIL AND ITS METABOLITES

Autopsy-tissues were obtained from eight patients who had last receive d menogaril (total cumulative dose, 175-1080 mg/m2) intravenously (one patient) or orally (seven patients) from 1 to 285 days prior to death . Tissue samples were assayed for menogaril and its metabolities by hi gh-pressure liquid chromatography. Unchanged menogaril was found only in a single lung-tissue sample from a patient who had died <24 h after receiving his last treatment. N-Demethylmenogaril was found in two lu ng-tissue samples and in single samples of the thyroid, lymph node, pa ncreas, cerebellum, and tumor. The major menogaril metabolite found in human autopsy-tissues was 7-deoxynogarol. The highest 7-deoxynogarol concentrations were found in the large bowel (median, 201 ng/g), liver (median, 183 ng/g), and lung (median, 177 ng/g). The heart ranked as the 9th of 18 organs in median 7-deoxynogarol concentration, after the large bowel, liver, lung, tumor, thyroid, skeletal muscle, adrenal gl and, and kidney. The lowest concentrations were detected in brain tiss ue. Our results suggest that the low degree of cardiac toxicity and th e possible pulmonary toxicity of menogaril may be related to relative tissue concentrations of menogaril metabolites. Tumor 7-deoxynogarol c oncentrations were comparable with those in normal tissues, except tha t concentrations in intracerebral tumors were higher than those in the normal brain. Tissue 7-deoxynogarol concentrations appeared to be dir ectly related to the cumulative dose and inversely related to the time from the last treatment to death; the value obtained by dividing dose by time correlated (P < 0.05) with tissue 7-deoxynogarol concentratio ns.