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Title of Journal: Eur J Clin Pharmacol

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Abbravation: European Journal of Clinical Pharmacology

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Springer-Verlag

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DOI

10.1002/ca.980010110

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1432-1041

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Identification of cytochrome P450 isoforms involve

Authors: KyoungAh Kim Jaegul Chung DongHae Jung JiYoung Park
Publish Date: 2004/09/08
Volume: 60, Issue: 8, Pages: 575-581
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Abstract

Objective The purpose of the present study was to elucidate the cytochrome P450 P450 isoforms involved in the metabolism of loperamide LOP to Ndemethylated LOP DLOP in human liver microsomes Methods Three established approaches were used to identify the P450 isoforms responsible for LOP Ndemethylation using human liver microsomes and cDNAexpressed P450 isoforms 1 correlation of LOP Ndemethylation activity with marker P450 activities in a panel of human liver microsomes 2 inhibition of enzyme activity by P450selective inhibitors and 3 measurement of DLOP formation by cDNAexpressed P450 isoforms The relative contribution of P450 isoforms involved in LOP Ndemethylation in human liver microsomes were estimated by applying relative activity factor RAF values Results The formation rate of DLOP showed biphasic kinetics suggesting the involvement of multiple P450 isoforms Apparent Km and Vmax values were 211 μM and 1223 pmol/min per milligram of protein for the highaffinity component and 839 μM and 4120 pmol/min per milligram of protein for the lowaffinity component respectively Of the cDNAexpressed P450 s tested CYP2B6 CYP2C8 CYP2D6 and CYP3A4 catalyzed LOP Ndemethylation LOP Ndemethylation was significantly inhibited when coincubated with quercetin a CYP2C8 inhibitor and ketoconazole a CYP3A4 inhibitor by 40 and 90 respectively but other chemical inhibitors tested showed weak or no significant inhibition DLOP formation was highly correlated with CYP3A4catalyzed midazolam 1hydroxylation rs=0829 P001 CYP2B6catalzyed 7ethoxy4trifluoromethylcoumarin Odeethylation rs=0691 P005 and CYP2C8catalyzed paclitaxel 6αhydroxylation rs=0797 P005 Conclusion CYP2B6 CYP2C8 CYP2D6 and CYP3A4 catalyze LOP Ndemethylation in human liver microsomes and among them CYP2C8 and CYP3A4 may play a crucial role in LOP metabolism at the therapeutic concentrations of LOP Coadministration of these P450 inhibitors may cause drug interactions with LOP However the clinical significance of potential interaction of LOP metabolism by CYP2C8 and CYP3A4 inhibitors should be studied further

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