Effects of oral curcumin on the pharmacokinetics of intravenous and oral etoposide in rats: possible role of intestinal CYP3A and P-gp inhibition by curcumin

• Published in: Biopharmaceutics & drug disposition 2011-05, Vol.32 (4), p.245-251
• Main Authors: Lee, Chong-Ki, Ki, Sung-Hwan, Choi, Jun-Shik
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Antineoplastic Agents - pharmacology; Antineoplastic Agents, Phytogenic - administration & dosage; Antineoplastic Agents, Phytogenic - pharmacology; ATP Binding Cassette Transporter, Subfamily B, Member 1 - antagonists & inhibitors; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism; bioavailability; curcumin; Curcumin - administration & dosage; Curcumin - pharmacology; CYP3A; Cytochrome P-450 CYP3A - physiology; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; etoposide; Etoposide - administration & dosage; Etoposide - pharmacokinetics; Etoposide - pharmacology; Fluorescent Dyes - pharmacokinetics; Injections, Intravenous; Intestinal Mucosa - metabolism; Intestines - drug effects; Male; P-gp; pharmacokinetics; Rats; Rats, Sprague-Dawley; Rhodamine 123 - pharmacokinetics
• ISSN: 0142-2782; 1099-081X
• DOI: 10.1002/bdd.754

This study aimed to investigate the effects of oral curcumin on the pharmacokinetics of intravenous and oral etoposide in rats. Intravenous (6 mg/kg) or oral (2 mg/kg) etoposide was administered to rats in the absence and the presence of oral curcumin (0.4, 2 or 8 mg/kg). The effects of curcumin on the P‐glycoprotein (P‐gp) and CYP3A4 activity was also evaluated. Curcumin inhibited CYP3A4 enzyme activity with a 50% inhibition concentration (IC50) of 2.7 µM. In addition, curcumin (10 µm) significantly enhanced the cellular accumulation of rhodamine‐123 in MCF‐7/ADR cells overexpressing P‐gp. Compared with the control group (given etoposide alone), curcumin (2 or 8 mg/kg) increased significantly the oral bioavailability (AUC and Cmax) of etoposide. Consequently, the extent of absolute oral bioavailability (F) of etoposide with curcumin was significantly enhanced compared with that in the control group. In contrast, curcumin did not affect the pharmacokinetics of etoposide after intravenous administration. Therefore, the enhanced oral bioavailability of etoposide in the presence of curcumin might be due mainly to inhibition of the P‐gp efflux pump in the small intestine and possibly by reduced first‐pass metabolism of etoposide in the small intestine by inhibition of CYP3A activity in rats. The combined use of curcumin may be helpful to improve the F of etoposide in chemotherapeutic applications. Copyright © 2011 John Wiley & Sons, Ltd.