Regular ArticleMeasurement of Liver Microsomal Cytochrome P450 (CYP2D6) Activity Using [O-methyl-14C] Dextromethorphan
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Effects of lobeline and reboxetine, fluoxetine, or bupropion combination on depression-like behaviors in mice
2015, Pharmacology Biochemistry and BehaviorCitation Excerpt :Although we have not analyzed drug levels to support a pharmacokinetic mechanism of drug–drug interaction, the enhanced antidepressant-like effects of the present study were less likely due to changes in hepatic metabolism. Lobeline is a potent inhibitor of cytochrome P450 2D6 (CYP2D6) (Rodrigues et al., 1994) which may increase plasma levels of drugs that are primarily metabolized by CYP2D6. However, metabolism of reboxetine, fluoxetine, or bupropion is not dependent on CYP2D6 (Hiemke and Härtter, 2000; Jefferson et al., 2005; Wienkers et al., 1999), indicating plasma levels of these antidepressants should not be affected by co-administration with lobeline.
High throughput P450 inhibition screens in early drug discovery
2005, Drug Discovery TodayCitation Excerpt :Table 2 provides a comparison of these methods with higher throughput radioactivity and optical methods. Radioactivity-based methods rely on 3H- or 14C-labeled drug substrates, which are selectively oxidized by the P450 isozyme of interest [29]. The metabolite is separated from the remaining substrate by HPLC and quantified via radiochemical detection.
High-Throughput Screening for Stability and Inhibitory Activity of Compounds toward Cytochrome P450-Mediated Metabolism
2004, Journal of Pharmaceutical SciencesCitation Excerpt :Assays using radiolabeled substrates have been developed for use in CYP inhibition screens.96–98 Fully automated radiometric inhibition assays have been developed for CYP1A2, 2D6, 2C9, 2C19, and 3A4 using phenacetin,97 dextromethorphan,106 naproxen,107 diazepam,108 and erythromycin,109 respectively, in which the O‐ or N‐alkyl group contained [14C]. The major disadvantage of these methods is that they require a solid‐phase extraction for separating metabolites from parent compounds before analysis, and therefore renders some of these approaches inadequate for high‐throughput screening.