Abstract
The in vitro and in vivo metabolism ofN-[1(R)-(1,3-benzodioxol-5-yl)butyl]-3,3-diethyl-2(S)-[4-[(4-methyl-1-piperazinyl)carbonyl]phenoxy]-4-oxo-1-azetidinecarboxamide (L-694,458) was studied in male Sprague-Dawley rats and rhesus monkeys. Analysis by LC-MS/MS and NMR revealed that the major metabolite generated in incubations with rat liver microsomes resulted fromN-oxidation of the piperazine group, while the major metabolite generated in monkey liver microsomes was the catechol that resulted from O-dealkylation of the methylenedioxyphenyl group. Other metabolites observed in these incubations include the piperazine N-desmethyl, several monohydroxylated derivatives of the parent compound, and three products that resulted from cleavage of the β-lactam ring. Incubations of parent compound with rat hepatocytes in culture generated two major metabolites that resulted from cleavage of the piperazine ring with the loss of an ethylene group from one side of the ring; one of these metabolites retained the piperazine N-methyl group, while the other did not. The metabolite profiles in vivo were similar to those observed in vitro, but they were much more complex owing to secondary and, in some cases, tertiary biotransformations of many of the primary metabolites. Bile obtained from orally dosed rats contained more than 40 parent-related components, and many of these metabolites had arisen from piperazine ring cleavage.
Footnotes
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Send reprint requests to: Dr. Debra Luffer-Atlas, Department of Drug Metabolism, Merck Research Laboratories, P.O. Box 2000, RY80-L109, Rahway, NJ 07065.
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↵2 L-694,458 has been licensed to DuPont Merck and is also known as DMP 777.
- Abbreviations used are::
- HLE
- human leukocyte elastase
- TFA
- trifluoroacetic acid
- DMSO
- dimethyl sulfoxide
- LC-MS
- liquid chromatography-mass spectrometry
- API
- atmospheric pressure ionization
- TIC
- total ion current
- EIC
- extracted ion current
- TIS
- turbo-ionspray
- CID
- collisionally induced dissociation
- SIF
- source-induced fragmentation
- CYP
- cytochrome P450
- Received December 23, 1996.
- Accepted April 29, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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