DETERMINATION OF CYTOCHROME-P450 3A4 5 ACTIVITY IN-VIVO WITH DEXTROMETHORPHAN N-DEMETHYLATION/

Dextromethorphan is used widely in vivo to phenotype the polymorphical ly expressed cytochrome P450 (CYP) 2D6. Dextromethorphan is N-demethyl ated in vitro to 3-methoxymorphinan by human CYP3A4/5. We examined whe ther the dextromethorphan/3-methoxymorphinan urinary metabolic ratio ( MR) could be used as an in vivo probe of CYP3A. Urinary excretion of 3 -methoxymorphinan was excretion rate-limited in extensive metabolizers of CYP2D6, which necessitated a longer urine collection, 0 to 72 hour s, to obtain true MR values for CYP3A. The urine excretion of dextrome thorphan and 3-methoxymorphinan was delayed in poor metabolizers of CY P2D6 but appeared to be formation rate-limited. The delayed excretion in poor metabolizers necessitated longer urine collection intervals, 0 to 11 days, to estimate the true CYP3A MR and 0 to 8 days to estimate the true CYP2D6 MR. However, a 72-hour collection in poor metabolizer s was used as an index of the true dextromethorphan/3-methoxymorphinan MR. Rifampin (300 mg b.i.d. for 7 days) significantly reduced the 0- to 72-hour dextromethorphan/3-methoxymorphinan MR consistent with an 8 30% (+/-1808%) induction of CYP3A activity (n=8), whereas erythromycin (250 mg q.i.d. for 7 days) significantly increased the dextromethorph an/3-methoxymorphinan MR, corresponding to a 34%+/-44% inhibition of a ctivity (n=7) in extensive metabolizers and poor metabolizers. The cha nges in CYP3A activity were independent of CYP2D6 phenotype and were a lso observed after 24- and 48-hour urine collections in extensive meta bolizers and poor metabolizers. In addition, MRs reflecting CYP2D6 and CYP3A were not significantly correlated. We conclude that the commonl y used antitussive dextromethorphan can be used Is an in vivo marker o f CYP3A and CYP2D6 activity.