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Drug Metabolism and Disposition Fast Forward
First published on October 4, 2006; DOI: 10.1124/dmd.106.012088

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Received for publication July 20, 2006.
Revised September 27, 2006.
Accepted for publication September 29, 2006.

Identification of human cytochrome P450 isozymes involved in diphenhydramine N-demethylation

Tomoko Akutsu 1*, Kaoru Kobayashi 1, Koichi Sakurada 2, Hiroshi Ikegaya 2, Tomomi Furihata 1, Kan Chiba 1

1 Chiba University 2 National Research Institute of Police Science

* Address correspondence to: E-mail: tomoko{at}nrips.go.jp

Abstract

Diphenhydramine is widely used as an over-the-counter antihistamine. However, the specific human cytochrome P450 (P450) isozymes that mediate the metabolism of diphenhydramine in the range of clinically relevant concentrations (0.14 to 0.77 µM) remain unclear. Therefore, P450 isozymes involved in N-demethylation, a main metabolic pathway of diphenhydramine, were identified by a liquid chromatography-mass spectrometry method developed in our laboratory. Among 14 recombinant P450 isozymes, CYP2D6 showed the highest activity of diphenhydramine N-demethylation (0.69 pmol/min/pmol P450) at 0.5 µM. CYP2D6 catalyzed diphenhydramine N-demethylation as a high-affinity P450 isozyme, the Km value of which was 1.12 ± 0.21 µM. In addition, CYP1A2, CYP2C9 and CYP2C19 were identified as low-affinity components. In human liver microsomes, involvement of CYP2D6, CYP1A2, CYP2C9 and CYP2C19 in diphenhydramine N-demethylation was confirmed by using P450-isozyme specific inhibitors. In addition, contributions of these P450 isozymes estimated by the relative activity factor were in good agreement with the results of inhibition studies. Although an inhibitory effect of diphenhydramine on the metabolic activity of CYP2D6 has been reported previously, the results of the present study suggest that it is not only a potent inhibitor but also a high-affinity substrate of CYP2D6. Therefore, it is worthy to mention that the sedative effect of diphenhydramine might be caused by co-administration of CYP2D6 substrate(s)/inhibitor(s). In addition, large differences in the metabolic activities of CYP2D6, and those of CYP1A2, CYP2C9 and CYP2C19 could cause the individual differences in anti-allergic efficacy and sedative effect of diphenhydramine.


Key words: CYP2D, cytochrome P450 catalyzed oxidations, cytochrome P450 isoforms, drug disposition, human CYP enzymes, liver microsomes, mass spectrometry, pharmacokinetics, recombinant proteins




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