Effect of dextromethorphan on CYP450 isoforms activity of rats

Dextromethorphan at high doses has phencyclidine-like effects on the NMDA receptor system; recreational use of high doses has been found to cause mania and hallucinations. In order to investigate the effects of dextromethorphan on the metabolic capacity of cytochrome P450 (CYP) enzymes, a cocktail method was employed to evaluate the activities of CYP2B1, CYP2D1, CYP1A2, CYP3A2, CYP2C11. The rats were randomly divided into dextromethorphan group (Low, Medium, High) and control group. The dextromethorphan group rats were given 12, 24, 48 mg/kg (Low, Medium, High) dextromethorphan by continuous intragastric administration for 7 days. Five probe drugs bupropion, metroprolol, phenacetin, testosterone and tolbutamide were given to rats through intragastric administration, and the plasma concentrations were determined by UPLC-MS/MS. Statistical pharmacokinetics difference for metroprolol, phenacetin and testosterone in rats were observed by comparing dextromethorphan group with control group. Continuous 7 days-intragastric administration of dextromethorphan inhibits the activities of CYP2D1 of rats. Enzyme inhibition by co-administered drugs and genetic variations of their expression can increase the risk of adverse reactions. Additionally, continuous 7 days-intragastric administration of dextromethorphan may not cause hepatotoxicity.