Evaluation of In Vitro Cytochrome P450 Inhibition and In Vitro Fate of Structurally Diverse N-Oxide Metabolites: Case Studies with Clozapine, Levofloxacin, Roflumilast, Voriconazole and Zopiclone.
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Giri P, Naidu S, Patel N, Patel H, Srinivas NR
Evaluation of In Vitro Cytochrome P450 Inhibition and In Vitro Fate of Structurally Diverse N-Oxide Metabolites: Case Studies with Clozapine, Levofloxacin, Roflumilast, Voriconazole and Zopiclone.
Eur J Drug Metab Pharmacokinet. 2017 Aug;42(4):677-688. doi: 10.1007/s13318-016-0385-7.
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- 27853934 [ View in PubMed]
- Abstract
BACKGROUND AND OBJECTIVES: The role of metabolite(s) to elicit potential clinical drug-drug interaction (DDI) via cytochrome P450 enzymes (CYP) is gaining momentum. In this context, the role of N-oxides for in vitro CYP inhibition has not been evaluated. The objectives of this study were: (a) to examine in vitro CYP inhibition of N-oxides of clozapine, levofloxacin, roflumilast, voriconazole and zopiclone in a tiered approach and (b) evaluate in vitro fate of aforementioned N-oxides examined in recombinant CYPs, human microsomes and hepatocytes. METHODS: CYP enzymes evaluated in the work included: CYP1A2, 2B6, 2C9, 2C19, 2D6 and 3A4 using standard procedures for incubation with appropriate probe substrates. The initial cutoff for CYP inhibition was >/=50% using 2 and 10 microM concentrations of various N-oxide metabolites (Tier 1). IC50 values were constructed for the CYP pathway(s) that showed >/=50% inhibition (Tier 2). In addition, co-incubation of N-oxides with parent was performed to evaluate potentiation of CYP inhibition (Tier 3). RESULTS: N-oxides of clozapine (CYP2B6/2C19) and voriconazole (CYP2C9/3A4) showed CYP inhibition >/=50%. Clozapine-N-oxide inhibited CYP2B6 and CYP2C19 pathways with IC50 of 8.3 and 8.7 microM, respectively. Voriconazole-N-oxide inhibited CYP2B6 and CYP2C19 pathways with IC50 of 10.5 and 11.2 microM, respectively. Co-incubation of clozapine-N-oxide with clozapine potentiated CYP2B6/2C19 pathways; however, incubation of voriconazole-N-oxide with voriconazole did not appear to potentiate the CYP pathways because parent caused an inhibition of almost 80%. None of the N-oxides appeared to further undergo biotransformation as judged by the in vitro metabolic fate experiments (stage 2). CONCLUSIONS: Clinical DDI potential of specific CYP enzymes needs to be considered arising due to circulatory concentrations of certain N-oxides depending on the dose size and/or frequency of dosing of the respective parent drugs.
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