title: Green tea extract affects the cytochrome P450 3A activity and pharmacokinetics of simvastatin in rats.
abstract: Effects of green tea extract (GTE) on the activity of cytochrome P450 (CYP) enzymes and pharmacokinetics of simvastatin (SIM) were investigated in rats. Inhibitory effects of GTE on CYP3A activity were investigated in rat hepatic microsomes (RHM) using midazolam (MDZ) 1'-hydroxylation as a probe reaction. SD female rats received a single oral dose of GTE (400 mg/kg) or troleandomycin (TAO, a CYP3A selective inhibitor, 500 mg/kg), followed 30 min later by SIM (20 mg/kg). Plasma concentrations of SIM and its active metabolite, simvastatin acid, were determined up to 6 h after the SIM administration using LC/MS/MS. In RHM, GTE inhibited MDZ 1'-hydroxylation with IC₅₀ and K(i)(app) values of 12.5 and 18.8 µg/mL, respectively, in a noncompetitive manner. Area under plasma concentration-time curves for SIM in the GTE and TAO groups were increased by 3.4- and 10.2-fold, respectively, compared with the control. The maximum concentrations of SIM were higher in the GTE (3.3-fold) and TAO (9.5-fold) groups. GTE alters the pharmacokinetics of SIM, probably by inhibiting intestinal CYP3A.
authors.affiliation: Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka.
authors.forename: Shingen
authors.initials: S
authors.lastname: Misaka
authors.forename: Keisuke
authors.initials: K
authors.lastname: Kawabe
authors.forename: Satomi
authors.initials: S
authors.lastname: Onoue
authors.forename: José Pablo
authors.initials: JP
authors.lastname: Werba
authors.forename: Monica
authors.initials: M
authors.lastname: Giroli
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Shizuo
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000818:Animals; D028241:Camellia sinensis / Q000737:chemistry*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism*; D065692:Cytochrome P-450 CYP3A Inhibitors; D005260:Female; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008874:Midazolam / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D019821:Simvastatin / Q000493:pharmacokinetics*; D014217:Troleandomycin / Q000494:pharmacology
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D010936:Plant Extracts; D019821:Simvastatin; D014217:Troleandomycin; D051544:Cytochrome P-450 CYP3A; D008874:Midazolam