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Green Tea Extract Affects the Cytochrome P450 3A Activity and Pharmacokinetics of Simvastatin in Rats

  • MISAKA Shingen
    Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka
  • KAWABE Keisuke
    Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka
  • ONOUE Satomi
    Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka
  • WERBA José Pablo
    Centro Cardiologico Monzino IRCCS
  • GIROLI Monica
    Centro Cardiologico Monzino IRCCS
  • WATANABE Hiroshi
    Department of Clinical Pharmacology and Therapeutics, Hamamatsu University School of Medicine
  • YAMADA Shizuo
    Department of Pharmacokinetics and Pharmacodynamics, School of Pharmaceutical Sciences, University of Shizuoka

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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 Kiapp 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.<br>

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