BIODISTRIBUTION AND METABOLISM OF ORALLY-ADMINISTERED MITOZOLOMIDE IN MICE

The disposition and metabolism of two C-14-labeled species of Mitozolomide (Mz) were studied in healthy and in B16 melanoma-bearing mice after po administration of a 40 mg/kg dose. Urine was the main elimination 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 expired air of mice given [C-14]tetrazin Mz, indicating an extensive metabolism of the drug. Subsequent studies conducted only with the [C-14]chloroethyl species, showed that total radioactivity and Mz were rapidly distributed to plasma and tissues but that Mz levels decreased more rapidly than those of total radioactivity, thus indicating an early metabolism 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 first 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 significantly differ between control and B16-bearing mice. In the other part related to metabolic fate, we showed that among the urinary excretion products, unchanged Mz represented about one third of the eliminated radioactivity. Eight metabolites were separated by HPLC and five identified as degradation products of alkylated glutathione, namely thiodiacetic acid and its sulfoxide, S-carboxymethylcysteine and N-acetyl derivatives of S-carboxymethylcysteine and S-hydroxyethylcysteine. To sum up, at the first stage of metabolism, in vivo Mz degradation perfectly corroborated that described in vitro and at the second stage, paralleled that reported in our previous studies concerning the behavior in animals of the chloroethyl moieties of 2-chloroethyl nitrosoureas.