US EPA

7493199 

Journal Article 

Metabolism of [m-(2-dimethylamino)] ethoxy phenyl-N,N-dimethylcarbamate hydrochloride monitored by 1H nuclear magnetic resonance spectroscopy in in situ perfused rat liver 

Li, H; Miao, ZC; Wang, N; Ruan, JX 

1995 

1 

Zhongguo Yaolixue yu Dulixue Zazhi / Chinese Journal of Pharmacology and Toxicology
ISSN: 1000-3002 

9 

2 

140-145 

Chinese 

High-resolution 1H nuclear magnetic resonance (NMR) spectroscopy at 400 MHz had been used to monitor the metabolism of [m-(2-dimethylamino)] ethoxy phenyl-N,N-dimethyl carbamate hydrochloride (DMDMC), a new anticholinesterase drug, by the in situ perfused rat liver. Samples of perfusate removed at various times during the perfusion were detected qualitatively and quantitatively by the selective spin inversion recovery echo 1H NMR technique. These NMR spectra showed resonances from DMDMC and its metabolites, as well as those from organic metabolites released from the liver after addition of DMDMC (150 mg · L-1). Of the resonances in the spectra, four singlets, at 2.64, 2.86, 2.94 and 3.00 ppm, were likely to be most useful for identification and quantification of the parent drug and its metabolites because they were well-resolved and lacked multiplet structure. These singlets were corresponding to two N-CH3 groups of the carbamate chain of these compounds. The major metabolites were identified as hydroxylated DMDMC and N-demethylated DMDMC. Accordingly, these resonances were used to monitor the disappearance of DMDMC and the formation of its metabolites. The elimination half life of the parent drug was 112 min. The relative maximal formation of hydroxylated DMDMC was 0.49, and N-demethylated DMDMC was 0.26. Following pretreatment with phenobarbital for 4 d (80 mg · kg-1 · d-1), the metabolic rate of DMDMC was markedly increased in the liver, with an elimination half life of 54 min. In the meanwhile, the formation rates of the two metabolites in the perfused liver were also increased. The results indicated that oxidation of the side chain carbamate is the major fate of DMDMC in the in situ perfused rat liver and this metabolic reaction was stimulated in livers from rats pretreated with phenobarbital. 

[m-(2-dimethylamino)] ethoxy phenyl-N,N-dimethylcarbamate; anticholinesterase agent; high pressure liquid chromatography; in situ perfusion, liver; metabolite; nuclear magnetic resonance; pharmacokinetics; carbamic acid derivative; cholinesterase inhibitor; drug metabolite; n,n dimethylcarbamic acid 3 [2 (dimethylamino)ethoxy]phenyl ester; phenobarbital; unclassified drug; animal experiment; article; controlled study; drug elimination; drug half life; drug metabolism; drug oxidation; drug structure; high performance liquid chromatography; liver perfusion; nonhuman; nuclear magnetic resonance; rat