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Enzymes in addition to CYP3A4 and 3A5 mediate N-demethylation of dextromethorphan in human liver microsomes

✍ Scribed by Yi Wang; Jashvant D. Unadkat

Publisher: John Wiley and Sons
Year: 1999
Tongue: English
Weight: 169 KB
Volume: 20
Category: Article
ISSN: 0142-2782
DOI: 10.1002/(sici)1099-081x(199910)20:7<341::aid-bdd195>3.0.co;2-f

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✦ Synopsis

Both indinavir and troleandomycin (CYP3A inhibitors) are incapable of completely inhibiting dextromethorphan metabolism to 3-methoxymorphinan in human liver microsomes. It is hypothesized that CYPs in addition to CYP3A4 and 3A5 contribute to this biotransformation. The effect of CYP-selective inhibitors on the residual 3-methoxymorphinan activity in human liver microsomes (i.e. in the presence of 30 mM indinavir, a selective CYP3A4 and 3A5 inhibitor) was measured to identify these enzymes. At this concentration, indinavir completely inhibited the formation of 3-methoxymorphinan by rCYP3A4 and rCYP3A5. In addition, the formation kinetics of 3-methoxymorphinan in rCYPs was measured. Only CYP2B6, 2C8 and 2C18 were considered likely candidates as contributors to residual 3-methoxymorphinan activity. The residual 3-methoxymorphinan activity was highly correlated with CYP2B6 activity as measured by CYP2B6 antibody (r 2 =0.90, pB 0.001) and by orphenadrine (r 2 =0.97, p B 0.001), but was not correlated (r 2 =0.12, p\0.05) with CYP2C8 activity. Collectively, these findings suggest that CYP2B6 is a major contributor towards residual 3-methoxymorphinan activity, while CYP2C8 and 2C18 are either minor contributors or do not contribute to this metabolic process.

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