Abstract
Cytochrome P450 (P450) reaction phenotyping is a key process toward accurately determining the contribution of different P450s to the metabolism of new chemical entities. The significance of P450s to drug disposition has led to the identification of selective chemical and antibody inhibitors for individual P450 enzymes. Despite these advances, the maximal inhibition attainable is limited by the use of inhibitor concentrations that maintain selectivity for the individual P450s. Thus, most commercially available inhibitors produce a maximal inhibition of ∼80%. Herein, the combination of chemical plus antibody inhibitors is explored to find whether P450 3A could be selectively and completely (>99%) inhibited by using both inhibitors simultaneously.
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.108.023572.
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ABBREVIATIONS: P450, cytochrome P450; HLM, human liver microsomes; LC/MS/MS, liquid chromatography-tandem mass spectrometry; Km, Michaelis-Menten constant; Vmax, maximum velocity; Ki, inactivator concentration yielding at 0.5 theoretical maximum inhibition rate constant; KD, dissociation constant; AUC, area under the curve.
- Received July 25, 2008.
- Accepted August 28, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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