title: Oral intake of curcumin markedly activated CYP 3A4: in vivo and ex-vivo studies.
abstract: Curcumin, a specific secondary metabolite of Curcuma species, has potentials for a variety of beneficial health effects. It is nowadays used as a dietary supplement. Everolimus (EVL) is an immunosuppressant indicated for allograft rejection and cancer therapy, but with narrow therapeutic window. EVL is a substrate of P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4). This study investigated the effect of coadministration of curcumin on the pharmacokinetics of EVL in rats and the underlying mechanisms. EVL (0.5 mg/kg) was orally administered without and with 50 and 100 mg/kg of curcumin, respectively, in rats. Blood samples were collected at specific time points and EVL concentrations in blood were determined by QMS immunoassay. The underlying mechanisms were evaluated using cell model and recombinant CYP 3A4 isozyme. The results indicated that 50 and 100 mg/kg of curcumin significantly decreased the AUC0-540 of EVL by 70.6% and 71.5%, respectively, and both dosages reduced the Cmax of EVL by 76.7%. Mechanism studies revealed that CYP3A4 was markedly activated by curcumin metabolites, which apparently overrode the inhibition effects of curcumin on P-gp. In conclusion, oral intake of curcumin significantly decreased the bioavailability of EVL, a probe substrate of P-gp/CYP 3A4, mainly through marked activation on CYP 3A4.
authors.affiliation: 1] School of Pharmacy, China Medical University, Taichung, Taiwan 404, R.O.C. [2] Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan 404, R.O.C.
authors.forename: Yow-Wen
authors.initials: YW
authors.lastname: Hsieh
authors.affiliation: 1] School of Pharmacy, China Medical University, Taichung, Taiwan 404, R.O.C. [2] Department of Pharmacy, China Medical University Hospital, Taichung, Taiwan 404, R.O.C.
authors.forename: Ching-Ya
authors.initials: CY
authors.lastname: Huang
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan 404, R.O.C.
authors.forename: Shih-Ying
authors.initials: SY
authors.lastname: Yang
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan 404, R.O.C.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Peng
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan 404, R.O.C.
authors.forename: Chung-Ping
authors.initials: CP
authors.lastname: Yu
authors.affiliation: School of Pharmacy, China Medical University, Taichung, Taiwan 404, R.O.C.
authors.forename: Pei-Dawn Lee
authors.initials: PD
authors.lastname: Chao
authors.affiliation: 1] School of Pharmacy, China Medical University, Taichung, Taiwan 404, R.O.C. [2] Department of Medical Research, China Medical University Hospital, Taichung, Taiwan 404, R.O.C.
authors.forename: Yu-Chi
authors.initials: YC
authors.lastname: Hou
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D045744:Cell Line, Tumor; D003474:Curcumin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A / Q000096:biosynthesis* / Q000235:genetics; D004347:Drug Interactions; D000068338:Everolimus; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051381:Rats; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000068338:Everolimus; D051544:Cytochrome P-450 CYP3A; D003474:Curcumin; D020123:Sirolimus