No abstract

Mitotane is an important adrenalytic drug for the treatment of adrenal cancer whose use is limited by toxicity. Reports from another laboratory indicated that a methylated homolog of Mitotane (Mitometh) tested in guinea pigs possessed comparable adrenalytic activity but was less toxic than Mitotane. This observation prompted us to undertake a comparative study of these two drugs on the basis that Mitometh may be a superior agent for the treatment of adrenal cancer. Preliminary studies in guinea pigs failed to show a significant adrenalytic effect for either Mitotane or Mitometh. Thus, we extended the study to 13 mongrel dogs weighing 12-15 kg that were treated daily with Mitometh or Mitotane (50-100 mg/kg) for 6 or 12 days. Cortisol decreased to undetectable levels and adrenocorticotropic hormone (ACTH) rose to 10 times the baseline levels within 72 h in Mitotane-treated animals. Despite the achievement of similar drug levels, Mitometh treatment in dogs failed to suppress cortisol or increase ACTH. To determine whether these differences were due to differences in bioavailability, we measured the relative concentration of Mitotane and Mitometh in homogenates of adrenal cortex obtained from Mitotane- and Mitometh-treated dogs. The adrenal concentration of Mitometh determined in Mitometh-treated dogs was 5 times higher than the concentration of Mitotane measured in Mitotane-treated animals. Whereas the adrenal glands of Mitotane-treated dogs showed hemorrhage and necrosis, the Mitometh-treated animals showed no adrenal damage. Despite the lack of adrenalytic activity, Mitometh maintained its toxicity as demonstrated by microscopic evidence of hepatic necrosis and an increase in hepatic enzymes. The adrenalytic effects of both agents was also studied in vitro using a human functioning adrenal cortical carcinoma cell line, NCI-H295. Whereas Mitotane strongly suppressed cell growth, Mitometh had a weaker effect. We conclude that Mitometh is not likely to be effective in the therapy of adrenal cancer. Moreover, the results of this study are supportive of the view that metabolic transformation of Mitotane is in some way linked to its adrenalytic action.

No abstract

In studies conducted to determine the fate of methomyl in goat, chicken, and monkey, an unknown highly polar, acidic metabolite was found in the urine/excreta of all three animals. The metabolite was purified by HPLC and analyzed by microcolumn LC/MS with electrospray ionization and by NMR. A Hypercarb porous graphitic carbon HPLC column was used for purification and LC/MS, since the unknown was unretained on conventional reversed phase HPLC columns. [ 14 C]Methomyl was used as radiotracer, and [ 13 C]methomyl was added at the 50% level to facilitate metabolite identification. The molecular weight of the metabolite was determined by LC/MS-electrospray, using positive and negative ionization, and structurally useful fragment ions were obtained in both modes by in-source collision-induced dissociation (CID). High-resolution accurate mass measurements of the MH + doublet allowed assignment of the elemental composition. NMR data showed the presence of methyl, methylene, and methine protons with coupling observed between 13 C and the methyl and methine protons. From these data, the structure was determined to be an unusual double conjugate of acetonitrile (a degradate of methomyl), involving conjugation with both cysteine and sulfate.