STUDIES ON THE METABOLIC-FATE OF CARACEMIDE, AN EXPERIMENTAL ANTITUMOR AGENT, IN THE RAT - EVIDENCE FOR THE RELEASE OF METHYL ISOCYANATE INVIVO

Following administration to rats of a single ip dose (6.6 mg kg-1) of the investigational antitumor agent caracemide (N-acetyl-N, O-bis[meth ylcarbamoyl]hydroxylamine), the mercapturic acid derivative N-acetyl-S -(N-methylcarbamoyl)cysteine (AMCC) was identified in urine by thermos pray LC-MS. Quantification of this conjugate was carried out by stable isotope dilution thermospray LC-MS, which indicated that the fraction of the caracemide dose recovered as AMCC in 24-h urine collections wa s 54.0 +/- 5.5% (n = 4). Since AMCC is known to represent a major urin ary metabolite of methyl isocyanate (MIC) in the rat, the results of t his study support the contention that caracemide yields MIC as a toxic intermediate in vivo. Furthermore, with the aid of a specifically deu terium-labeled analog of caracemide ([carbamoyloxy-(CH3)-H-2]carcemide ), it was shown that the methylcarbamoyl group of AMCC derived from bo th the O-methylcarbamoyl (72%) and N-methylcarbamoyl (28%) side chains of the drug. In view of these findings, it is concluded that caracemi de acts as a latent form of MIC in vivo and that this reactive isocyan ate (or labile S-linked conjugates thereof) may contribute to the anti tumor properties and/or adverse side-effects of caracemide.