Studies on the metabolic fate of caracemide, an experimental antitumor agent, in the rat. Evidence for the release of methyl isocyanate in vivo.
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[methylcarbamoyl]hydroxylamine), the mercapturic acid derivative N-acetyl-S-(N-methylcarbamoyl)cysteine (AMCC) was identified in urine by thermospray 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 was 54.0 +/- 5.5% (n = 4). Since AMCC is known to represent a major urinary metabolite of methyl isocyanate (MIC) in the rat, the results of this study support the contention that caracemide yields MIC as a toxic intermediate in vivo. Furthermore, with the aid of a specifically deuterium-labeled analog of caracemide ([carbamoyloxy-C2H3]caracemide), it was shown that the methylcarbamoyl group of AMCC derived from both the O-methylcarbamoyl (72%) and N-methylcarbamoyl (28%) side chains of the drug. In view of these findings, it is concluded that caracemide acts as a latent form of MIC in vivo and that this reactive isocyanate (or labile S-linked conjugates thereof) may contribute to the antitumor properties and/or adverse side-effects of caracemide.
Slatter
J G
JG
Department of Medicinal Chemistry, School of Pharmacy, University of Washington, Seattle 98195.
Davis
M R
MR
Han
D H
DH
Pearson
P G
PG
Baillie
T A
TA
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000652:urine; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000652:urine; D003485:Cyanates / Q000493:pharmacokinetics* / Q000633:toxicity / Q000652:urine; D006918:Hydroxyurea / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000652:urine; D017953:Isocyanates; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
D000970:Antineoplastic Agents; D003485:Cyanates; D017953:Isocyanates; C052469:N-acetyl-S-(N-methylcarbamoyl)cysteine; C008461:methyl isocyanate; C044466:caracemide; D000111:Acetylcysteine; D006918:Hydroxyurea