Received for publication May 17, 2006.
Revised October 16, 2006.
Accepted for publication October 17, 2006.

Impact of Curcumin-induced Changes in P-gp and CYP3A Expression on the Pharmacokinetics of Peroral Celiprolol and Midazolam in Rats

Abstract

The aim of this study was to evaluate whether curcumin could modulate P-gp and CYP3A expression, and in turn modify the pharmacokinetic profiles of P-gp and CYP3A substrates in the male SD rats. Intragastric gavage of the rats with 60 mg/kg of curcumin for 4 consecutive days led to a down-regulation of the intestinal P-gp level. There was a concomitant up-regulation of hepatic P-gp level but the renal P-gp level was unaffected. Curcumin also attenuated the CYP3A level in the small intestine, but induced CYP3A expression in the liver and kidney. The regular curcumin consumption also caused the C_max and area under the concentration-time curve (AUC_0-8 and total AUC) of peroral celiprolol (a P-gp substrate with negligible CYP metabolism) at 30 mg/kg to increase, but the apparent oral clearance (CL_oral) of the drug was reduced. Similarly, rats treated with curcumin for 4 consecutive days showed higher AUC (AUC_0-4 and total AUC) and lower CL_oral for peroral midazolam (a CYP3A substrate that does not interact with the P-gp) at 20 mg/kg in comparison with vehicle-treated rats. In contrast, curcumin administered 30 min before the respective drug treatments did not significantly modify the pharmacokinetic parameters of the drugs. Analysis of the data suggests that the changes in the pharmacokinetic profiles of peroral celiprolol and midazolam in the rat model were contributed mainly by the curcumin-mediated down-regulation of intestinal P-gp and CYP3A protein levels, respectively.

Key words: ABC transporters, bioavailability, CYP expression, CYP3A, cytochrome P450, cytochrome P450 regulation, HPLC, microsomes, p-glycoprotein, pharmacokinetics

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