title: Epigallocatechin-3-gallate decreases the transport and metabolism of simvastatin in rats.
abstract: 1. This study aimed to investigate the potential impact of epigallocatechin-3-gallate (EGCG) on the pharmacokinetic behaviors of simvastatin and its metabolite simvastatin acid and explored the possible role of metabolizing enzymes and transporters of this food-drug interaction. 2. Female SD rats were intravenously administered with EGCG (5 mg/kg), ketoconazole (10 mg/kg) and rifampin (10 mg/kg), followed by intravenous administration of 2 mg/kg simvastatin. In vitro, the effects of EGCG on Cytochrome P450 enzymes (CYP450) and organic anion transporting polypeptides (OATPs) were studied using human hepatic microsomes and human embryonic kidney 293 (HEK293) cells overexpressing OATP1B1 or OATP1B3. The results showed that areas under concentration-time (AUC) curves of simvastatin and simvastatin acid increased by 2.21- and 1.4-fold while the clearance was reduced by 2.29- and 1.4-fold, respectively, when co-administered with EGCG. In vitro experiments suggested the inhibitory effect of EGCG on CYP enzymes (IC50: 18.37 ± 1.36 μM, 26.08 ± 1.51 μM for simvastatin and simvastatin acid, respectively). Simvastatin transport by OATP1B1 and OATP1B3 was also inhibited by EGCG (IC50: 8.68 ± 1.27 μM and 22.67 ± 1.42 μM, respectively). 3. The presently reported novel food-drug interaction between EGCG and simvastatin involves the inhibition of not only CYP450 enzymes but also OATPs by EGCG.
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yang
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Qiuyang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Yue
authors.initials: Y
authors.lastname: Yang
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Jiaqiu
authors.initials: J
authors.lastname: Xu
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Ali
authors.initials: A
authors.lastname: Fan
authors.affiliation: b Department of Chemical Biology , Ernest Mario School of Pharmacy Rutgers, The State University of New Jersey , Piscataway , NJ , USA , and.
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Lu
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Jiayin
authors.initials: J
authors.lastname: Chen
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Di
authors.initials: D
authors.lastname: Zhao
authors.affiliation: c Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Jiye
authors.initials: J
authors.lastname: Aa
authors.affiliation: a Center of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University , Nanjing , China.
authors.forename: Xijing
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000378:metabolism*; D001692:Biological Transport; D002392:Catechin / Q000031:analogs & derivatives* / Q000378:metabolism; D005260:Female; D018565:Food-Drug Interactions; D057809:HEK293 Cells; D006801:Humans; D027361:Organic Anion Transporters / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000031:analogs & derivatives / Q000378:metabolism*
chemical_list: D000924:Anticholesteremic Agents; D027361:Organic Anion Transporters; D002392:Catechin; C063287:simvastatin acid; D019821:Simvastatin; C045651:epigallocatechin gallate
keywords: CYP450; OATPs; epigallocatechin-3-gallate; pharmacokinetics; simvastatin; simvastatin acid