Abstract
2,4-Dichloro-6-phenylphenoxyethylamine and 2-chloro-6-phenylphenoxyethylamine are effective, long-acting in vivo inhibitors of microsomal mono-oxygenases. Plasma and liver half-lives were found to be in the range of 110-130 min. Distribution studies show that DPEA1 and MPEA concentrate in liver, principally in the microsomal fraction, as unmetabolized amines. These observations offer an explanation for the long duration of action of DPEA and MPEA. They are relatively inactive substrates for the microsomal enzyme system and are excreted principally in the bile as unchanged amine (25-30%) or as an N-glucuronide conjugate (40-60%). The in vitro formation of deaminated metabolites (alcohol, acid, or aldehyde) required NADPH and oxygen as cofactors and microsomes as the enzyme source. α-Methyl-MPEA, an ineffective inhibitor of microsomal mono-oxygenases but an excellent substrate for microsomal deamination, yielded not only alcohol and ketone as metabolites but also the oxime of the ketone. Incorporation of isotope from 1802 into the alcohol and ketone (74 atom %) and oxime (96-99 atom % 18O) support the hypothesis that the microsomal deamination of primary amines occurs via an unstable carbinolamine intermediate.
Footnotes
- Received January 15, 1973.
- Copyright © 1973 by The American Society for Pharmacology and Experimental Therapeutics
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