Evaluation of Dextromethorphan Metabolism Using Hepatocytes from CYP2D6 Poor and Extensive Metabolizers

The results of low formations of dextrorphan (DXO) and 3-hydroxymorphinan (3-HM) in CYP2D6 PM hepatocytes incubated with dextromethorphan reflected the clinical data. Formation of 3-methoxymorphinan (3-MEM) normalized by CYP3A4/5 activity in the PM hepatocytes reached about 2.8-fold higher than that in CYP2D6 extensive metabolizer (EM) hepatocytes, which clearly showed the compensatory metabolic pathway of O-demethylation catalyzed by CYP2D6 as seen in clinical study. On the contrary, in the condition of the EM hepatocytes with CYP2D6 inhibitors, the enhancement of 3-MEM formation was not observed. In phase II reaction, the glucuronide formation rate of DXO in the PM hepatocytes was lower than that in the EM hepatocytes, which was consistent with clinical data of DXO-glucuronide (DXO-glu) concentration. These results would suggest that CYP2D6 PM hepatocytes could be a good in vitro tool for estimating CYP2D6 PM pharmacokinetics.