Title: Metabolic interaction between rotundine and oxycodone in vitro
Abstract: AIM To investigate inhibitory and inducing potencies of rotundine (RTD) and oxycodone (OCD) on liver cytochrome P450 (CYP) isoforms,and assess the potential metabolic drug-drug interaction of the two drugs when they are clinically coadministrated. METHODS RTD and OCD (0-50 μmol·L-1) were incubated with human liver microsome for 20 min at a series of concentrations,in the presence of NADPH and a group of CYP probe substrates for CYP1A2,CYP2C9,CYP2C19,CYP2D6 and CYP3A4. CYP isoform-specific inhibitors were tested in parallel as positive controls. The relative activities of CYP isoforms were determined by analyzing the formation of the substrate metabolites using LC-MS. Subsequently the IC50 value was calculated for each CYP isoforms tested. The inhibitory potencies of RTD and OCD on CYP1A2,CYP2C9,CYP2D6 and CYP3A4 were then evaluated. RTD 20,200 and 2000 μg·L-1,OCD 2,20 and 200 μg·L-1 or CYP specific inducers were incubated with primary rat hepatocytes for 72 h,which was followed by incubating the hepatocytes with a group of CYP substrates for additional 60 min. The metabolic clearance for each substrate in incubates was measured,which was used to calculate the relative CYP activities of CYP1A and 3A. The data obtained from the groups treated with RTD and OCD were then compared with those from known inducers to assess their inducing potencies. RESULTS Under the experimental conditions applied in this study,OCD did not show any inhibitory or inducing potencies on all the CYP isoforms tested. RTD only demonstrated a moderate inhibitory potency on CYP2D6,with IC50 of 3.72 μmol·L-1. CONCLUSIONRTD is classified as a moderate inhibitor of CYP2D6. Inhibition of CYP2D6 by RTD at a plasma level equal to or higher than its IC50 (3.72 μmol·L-1) may result in the decrement of OCD O-demethylation in vivo. However,it is expected that the metabolic interaction between RTD and OCD will not be clinically significant at the ordinary clinical dose levels of these two drugs.
Publication Year: 2009
Publication Date: 2009-01-01
Language: en
Type: article
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