CYP2C9 mediates the herb-drug interaction of curcumin with naproxen in rats

Both curcumin and naproxen possess the activity of pain relief, which makes it possible to co-administrate these drugs in the same prescription. This study aimed to assess the potential pharmacokinetic interaction of naproxen with curcumin in rats. Sprague-Dawley (SD) rats were orally administrated with naproxen (10 mg/kg body weight) and curcumin (10 or 20 mg/kg, body weight) synchronously or successively with a single administration of naproxen as the control group. The plasma concentration of naproxen was analyzed with liquid chromatography tandem mass spectrometry and the plasma concentration-time curve was established to obtain the pharmacokinetic parameters. In vitro, the metabolic stability of naproxen and the activity of CYP2C9 was assessed in rat liver microsome to reveal the potential mechanism. Both synchronous and successive co-administration of naproxen and curcumin induced increased maximum concentration (Cmax), area under the curve (AUC0-t), half-life (t1/2) and reduced clearance rate (CLF) of naproxen in rats, and the effect of curcumin was enhanced with its increasing concentration. In vitro, curcumin (10 and 20 mg/kg) was found to enhance the metabolic stability of naproxen (half-life from 29.7 ± 1.34 to 41.8 ± 5.07 and 46.9 ± 3.33 min) and significantly inhibited the activity of CYP2C9 with the IC50 of 16.36 μmol/L (P < 0.05). A combination of naproxen and curcumin would induce pharmacokinetic interaction, which increased the systemic exposure of naproxen. The concentration-dependent inhibition of CYP2C9 by curcumin was the potential mechanism underlying the drug-herb interaction.