Human autopsy-tissue distribution of menogaril and its metabolites

Abstract

Autopsy-tissues were obtained from eight patients who had last received 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 high-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 lung-tissue samples and in single samples of the thyroid, lymph node, pancreas, 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 gland, and kidney. The lowest concentrations were detected in brain tissue. Our results suggest that the low degree of cardiac toxicity and the possible pulmonary toxicity of menogaril may be related to relative tissue concentrations of menogaril metabolites. Tumor 7-deoxynogarol concentrations were comparable with those in normal tissues, except that concentrations in intracerebral tumors were higher than those in the normal brain. Tissue 7-deoxynogarol concentrations appeared to be directly 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 concentrations.

Comparative In Vitro Study of the Cytotoxic Effects of Doxorubicin’s Main Metabolites on Cardiac AC16 Cells Versus the Parent Drug

“…The predominant literature on DOX metabolites primarily focus on their detection, the characterization of patients’ pharmacokinetics profile, or, at most, the cytotoxic effect of one metabolite [ 4 , 5 , 9 , 10 , 20 , 21 , 39 ]. However, some pioneer studies, mainly from the group of Giorgio Minotti [ 9 , 10 , 20 ] or the 1988 work by Olson and co-workers [ 11 ] brought new perspectives on the influence of DOX metabolites on the cardiotoxicity of the parent drug.…”

“…This reduction step is catalysed by aldo/keto reductases or carbonyl reductases [ 7 , 8 ]. Regarding the previously mentioned study by Stewart and co-workers on post-mortem samples, the heart ranked 5th on DOXol accumulation [ 4 ], which shows the large cardiac permanence of both the parent drug and this metabolite. DOXol is more hydrophilic than DOX, which favours its retention within the cardiomyocytes after DOX metabolism [ 3 , 4 , 9 , 10 ].…”

“…Regarding the previously mentioned study by Stewart and co-workers on post-mortem samples, the heart ranked 5th on DOXol accumulation [ 4 ], which shows the large cardiac permanence of both the parent drug and this metabolite. DOXol is more hydrophilic than DOX, which favours its retention within the cardiomyocytes after DOX metabolism [ 3 , 4 , 9 , 10 ]. Finally, the working hypothesis that DOXol can contribute to DOX cardiotoxicity has been placed for a long time [ 11 , 12 ], and we also made research in the past to test that hypothesis [ 13 ].…”

“…Tissues obtained from autopsies of 35 patients who had been administered DOX before death in different time points of their lives, revealed that the heart exhibited the fourth-highest levels of DOX. The patients had received doses ranging from 30 to 670 mg/m 2 , and the interval since the last treatment varied between 1 and 931 days [ 4 ], showing DOX long permanence in the heart. In mice with tumours, after administering a single dose of 10 mg/kg DOX, the animal hearts exhibited the highest relative total tissue concentrations of DOX after 24 h [ 5 ].…”