Abstract
The aim of our study was to identify the form(s) of cytochrome P450 responsible for the metabolism of deramciclane, a new anxiolytic drug candidate. The main routes of biotransformation in hepatic microsomes were side chain modification (N-demethylation or total side chain cleavage) and hydroxylation at several points of the molecule. Although several cytochrome P450 forms were involved in the metabolism, the role of CYP2E1 should be emphasized, since it catalyzed almost all steps. Production of deramciclane metabolites was significantly inhibited by diethyl-dithiocarbamate and was elevated in liver microsomes of isoniazid-treated rats. Furthermore, cDNA-expressed rat CYP2E1 generated the metabolites formed by side chain modification and hydroxylation. Neither deramciclane nor its primary metabolite, N-desmethyl deramciclane were able to influence directly the activity of CYP2E1. However, during the biotransformation, one or more metabolites must have been formed which were potent inhibitors of CYP2E1.
Footnotes
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Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
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doi:10.1124/dmd.105.003772.
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ABBREVIATIONS: P450, cytochrome P450; HPLC, high-performance liquid chromatography; deramciclane, (1R,2S,4R)-(–)-2-phenyl-2-(2′-dimethylamino-ethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane; N-desmethyl-deramciclane (M4), (1R,2S,4R)-(–)-2-phenyl-2-(2′-methylamino-ethoxy)-1,7,7-trimethyl-bicyclo[2.2.1]heptane; 9-hydroxy-deramciclane (M5), (1R,2S,4R,7R)-2-(2′-dimethylamino-ethoxy)-2-phenyl-7-(hydroxy-methyl)-1,7-dimethylbicyclo[2.2.1]heptane; N-desmethyl 9-hydroxy-deramciclane (M2), (1R,2S,4R,7R)-2-(2′-methyl-amino-ethoxy)-2-phenyl-7-(hydroxy-methyl)-1,7-dimethyl-bicyclo[2.2.1]heptane; hydroxy-deramciclane II (M6), (1R,2S,4R)-(–)-2-phenyl-2-(2′-dimethylamino-ethoxy)-5 or 6-hydroxy-1,7,7-trimethyl-bicyclo[2.2.1]heptane; N-desmethyl hydroxy-deramciclane II (M3), (1R,2S,4R)-(–)-2-phenyl-2-(2′-methylamino-ethoxy)-5 or 6-hydroxy-1,7,7-trimethyl-bicyclo[2.2.1]heptane, phenylborneol, (1R,2S,4R)-(–)-2-hydroxy-2-phenyl-1,7,7-trimethyl-bicyclo[2.2.1]heptane.
- Received January 19, 2005.
- Accepted May 27, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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