title: High-Dose Metformin May Increase the Concentration of Atorvastatin in the Liver by Inhibition of Multidrug Resistance-Associated Protein 2.
abstract: In this study, we evaluated the effect of coadministered metformin on the biliary excretion and liver concentration of atorvastatin. To investigate the inhibitory effect of metformin on biliary efflux transporters, the transport of atorvastatin in MDCKII-MDR1, BCRP, and MRP2 was evaluated. The effects of metformin on the steady state liver concentration and biliary excretion of atorvastatin and 2-hydroxyatorvastatin were evaluated in SDR and Mrp2-deficient EHBR. Metformin did not inhibit the transport of atorvastatin via BCRP and MDR1. However, metformin significantly inhibited the transport of atorvastatin and 2-hydroxyatorvastatin via MRP2 (apparent IC50= 12 and 2 μM). Coadministered metformin significantly increased the Kp,liverand Cliver(1.7- and 1.6-fold) and decreased the biliary clearance of atorvastatin (2.7-fold) in SDR, but it did not affect the plasma concentration and total clearance of atorvastatin. Similar effects by metformin were observed for 2-hydroxyatorvastatin. In addition, coadministered metformin did not have any effect in EHBR. Therefore, coadministered metformin increases the liver concentration of atorvastatin via inhibition of the Mrp2 in rats, without affecting the plasma concentration. This "silent interaction" by metformin in atorvastatin and metformin combination therapy may be related to the unnoticeable pharmacological synergism or unpredicted side effects of atorvastatin in the liver.
authors.affiliation: Division of Biopharmaceutics, College of Pharmacy, Kyung Hee University, Seoul, South Korea; Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, South Korea.
authors.forename: Eunjung
authors.initials: E
authors.lastname: Shin
authors.affiliation: Division of Biopharmaceutics, College of Pharmacy, Kyung Hee University, Seoul, South Korea; Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, South Korea.
authors.forename: Naree
authors.initials: N
authors.lastname: Shin
authors.affiliation: Division of Biopharmaceutics, College of Pharmacy, Kyung Hee University, Seoul, South Korea.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Oh
authors.affiliation: Division of Biopharmaceutics, College of Pharmacy, Kyung Hee University, Seoul, South Korea; Department of Life and Nanopharmaceutical Sciences, Kyung Hee University, Seoul, South Korea. Electronic address: yj_lee@khu.ac.kr.
authors.forename: Young-Joo
authors.initials: YJ
authors.lastname: Lee
mesh_terms: D000818:Animals; D000069059:Atorvastatin / Q000008:administration & dosage / Q000378:metabolism*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D008687:Metformin / Q000008:administration & dosage / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000069059:Atorvastatin; D008687:Metformin; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins
keywords: MRP; biliary excretion; drug interactions; efflux pumps; permeability