Abstract
When incubated with human liver microsomes, 2-diethylaminoethyl-2,2-diphenylvalerate-HCl (SKF525A) undergoes cytochrome P450 (P450)-dependent oxidative N-deethylation to the secondary amine metabolite 2-ethylaminoethyl-2,2-diphenylvalerate (SKF8742). P450-selective inhibitors indicated CYP3As catalyzed this reaction, and the deethylation rate correlated best with the CYP3A activity across a range of human liver microsomes. SKF525A and its metabolite and primary amine analog all inhibited CYP2B6-, CYP2C9-, CYP2C19-, CYP2D6-, and CYP3A-selective reactions to varying degrees but had little effect on CYP1A2, CYP2A6, and CYP2E1 reactions. Only the inhibition of CYP3A showed major enhancement when the inhibitors were preincubated with NADPH-fortified microsomes, and the extent of metabolic intermediate (MI) complex formation approximated typical CYP3A content. Two “lost with time” SKF525A derivatives devoid of the ethylamine moiety, 2,2-diphenylpropylethanol (SKF-Alcohol) and 2,2-diphenylpropylacetic acid (SKF-Acid) did not form an MI complex and were identified as selective inhibitors of CYP2C9. Although without detectable metabolism, their CYP2C9 inhibition fitted best with a competitive mechanism. Thus, not all the human P450s are inhibited by SKF525A and related compounds, and the mechanisms contributing to those that are inhibited vary with the isoform. P450 MI-complex formation only seems to play a role with CYP3As.
Footnotes
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↵1 Cognizant of continuing historical precedence, the A (acid salt) has been retained in referring to SKF525A, but it has been omitted when referring to the secondary (SKF8742) and primary (SKF26754) amine derivatives.
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This work was supported in part by National Institutes of Health/National Institute of Neurological Disorders and Stroke Contract N01-NS-4-2359.
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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.108.023549.
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ABBREVIATIONS: P450, cytochrome P450; SKF525A, proadifen hydrochloride, 2-diethylaminoethyl-2,2-diphenylvalerate-HCl, β-diethylaminoethyldiphenylpropylacetate-HCl; SKF-Acid, 2,2-diphenylpropylacetic acid; SKF-Alcohol, 2,2-diphenylpropylethanol; MI, metabolic intermediate; SKF8742, 2-ethylaminoethyl-2,2-diphenylvalerate; SKF26754, aminoethyl-2,2-diphenylvalerate; HPLC, high-performance liquid chromatography.
- Received July 23, 2008.
- Accepted September 12, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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