Effect of colchicine on rat hepatic cytochrome P450 enzymes by cocktail probe drugs.

Colchicine (COL), an alkaloid derived from plants, has been used to treat gout, pseudogout and familial Mediterranean fever for several decades. The purpose of this study was to investigate the in vivo effect of COL on rat cytochrome P450 enzymes (CYP1A2, CYP2C9, CYP2C19 and CYP2D6) to assess its potential to interact with co-administered drugs. This was a randomized, double-blind, two-way crossover study with a 4-week washout period between the phases. Rats received COL via an irrigation stomach needle at a dose of 0.4 mg/kg once daily for consecutive 10 days. On the eleventh day, a cocktail solution at a dose of 4 ml/kg, which contained phenacetin (15.0 mg/kg), tolbutamide (3.0 mg/kg), omeprazole (15.0 mg/kg) and dextromethorphan (15.0mg/kg), was oral administered to all rats. Then 0.3 ml blood samples were collected at a set of time-points. The plasma concentrations of probe drugs were simultaneously determined by HPLC-MS/MS. Pharmacokinetic parameters simulated by DAS software were used for the evaluation of COL on the activities of rat CYP1A2, CYP2C9, CYP2C19 and CYP2D6 enzymes. Our study showed that COL administration induced CYP2C9 activity, causing a significant decrease in AUC(0-infinity) (P < 0.01) and t1/2 (P < 0.05) of tolbutamide, and a distinct increase in CL (P<0.01). Many pharmacokinetic parameters of dextromethorphan in COL-treated rats were affected significantly, which indicated that the metabolism of dextromethorphan in these treatment groups was evidently slowed down. However, there was no significant influence of pharmacokinetic parameters of phenacetin and omeprazole in COL-treated rats. The results from the present in vivo study suggested that COL showed no effects on rat CYP1A2 and CYP2C19, however, it demonstrated potential inductive effects on CYP2C9 and inhibitory effects on CYP2D6. Therefore, caution is needed when COL is co-administered with drugs metabolized by CYP2C9 or CYP2D6, which may result in altered plasma concentrations of these drugs and relevant drug-drug interactions.