BIODISTRIBUTION AND METABOLISM OF ORALLY-ADMINISTERED MITOZOLOMIDE INMICE

The disposition and metabolism of two C-14-labeled species of Mitozolo mide (Mz) were studied in healthy and in B16 melanoma-bearing mice aft er po administration of a 40 mg/kg dose. Urine was the main eliminatio n route of the radioactivity derived from [C-14]chloroethyl Mz whereas a major part of the radiocarbon was recovered as (CO2)-C-14 in the ex pired air of mice given [C-14]tetrazin Mz, indicating an extensive met abolism of the drug. Subsequent studies conducted only with the [C-14] chloroethyl species, showed that total radioactivity and Mz were rapid ly distributed to plasma and tissues but that Mz levels decreased more rapidly than those of total radioactivity, thus indicating an early m etabolism of the drug. It is noteworthy that B16 melanoma concentrated Mz and/or metabolites to the same extent as normal tissues except the brain. Elimination of Mz from all tissues including the tumor was fir st order with 8 t1/2 ranging from 1.52 to 2.03 hr. In the part of the study related to disposition, pharmacokinetic parameters did not signi ficantly differ between control and B16-bearing mice. In the other par t related to metabolic fate, we showed that among the urinary excretio n products, unchanged Mz represented about one third of the eliminated radioactivity. Eight metabolites were separated by HPLC and five iden tified as degradation products of alkylated glutathione, namely thiodi acetic acid and its sulfoxide, S-carboxymethylcysteine and N-acetyl de rivatives of S-carboxymethylcysteine and S-hydroxyethylcysteine. To su m up, at the first stage of metabolism, in vivo Mz degradation perfect ly corroborated that described in vitro and at the second stage, paral leled that reported in our previous studies concerning the behavior in animals of the chloroethyl moieties of 2-chloroethyl nitrosoureas.