title: The effect of the newly developed angiotensin receptor II antagonist fimasartan on the pharmacokinetics of atorvastatin in relation to OATP1B1 in healthy male volunteers.
abstract: OBJECTIVE
  Interactions between coadministered drugs may unfavorably affect pharmacokinetics. This study evaluated whether fimasartan, an angiotensin receptor II antagonist, affected the pharmacokinetics of atorvastatin.
  
  
  METHODS
  A randomized, open-label, 2-period, 2-sequence, crossover, multiple-dosing study was conducted with 24 healthy male volunteers. Twelve subjects received 80-mg atorvastatin once daily for 7 days; later, they received 80-mg atorvastatin with 240-mg fimasartan for 7 days. Twelve other subjects received the same drugs in the opposite sequence. Blood samples were collected scheduled intervals for 24 hours after the last dosing to determine plasma concentrations of atorvastatin acid, atorvastatin lactone, 2-hydroxy atorvastatin acid, and 2-hydroxy atorvastatin lactone.
  
  
  RESULTS
  Compared with atorvastatin alone, coadministration of fimasartan and atorvastatin increased the atorvastatin acid mean (95% confidence interval) maximum concentration (Cmax,ss) by 1.89-fold (1.49-2.39) and the area under the concentration curve (AUCτ,ss) by 1.19-fold (0.96-1.48). Fimasartan also increased the mean 2-hydroxy atorvastatin acid Cmax,ss and AUCτ,ss by 2.45-fold (1.80-3.35) and 1.42-fold (1.09-1.85), respectively. The Cmax,ss and AUCτ,ss of the lactone forms of atorvastatin showed smaller changes than those observed for the acidic forms.
  
  
  CONCLUSIONS
  We showed that fimasartan raised plasma atorvastatin concentrations. In vitro tests suggested that this effect may have been mediated by fimasartan inhibition of organic anion-transporting polypeptide 1B1.
authors.affiliation: Department of Pharmacology and Clinical Pharmacology, Seoul National University College of Medicine and Hospital, Seoul, Korea.
authors.forename: Kwang-Hee
authors.initials: KH
authors.lastname: Shin
authors.forename: Tae-Eun
authors.initials: TE
authors.lastname: Kim
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: Min Goo
authors.initials: MG
authors.lastname: Lee
authors.forename: Im-Sook
authors.initials: IS
authors.lastname: Song
authors.forename: Seo Hyun
authors.initials: SH
authors.lastname: Yoon
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Cho
authors.forename: In-Jin
authors.initials: IJ
authors.lastname: Jang
authors.forename: Sang-Goo
authors.initials: SG
authors.lastname: Shin
authors.forename: Kyung-Sang
authors.initials: KS
authors.lastname: Yu
mesh_terms: D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D019540:Area Under Curve; D000069059:Atorvastatin / Q000031:analogs & derivatives; D001713:Biphenyl Compounds / Q000494:pharmacology*; D018592:Cross-Over Studies; D004347:Drug Interactions / Q000502:physiology; D004970:Estrone / Q000031:analogs & derivatives / Q000378:metabolism; D006538:Heptanoic Acids / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D027361:Organic Anion Transporters / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000493:pharmacokinetics*; D018075:RNA, Complementary / Q000235:genetics; D013777:Tetrazoles / Q000494:pharmacology*; D055815:Young Adult
chemical_list: C518963:2-hydroxyatorvastatin; D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; D011743:Pyrimidines; D011758:Pyrroles; D018075:RNA, Complementary; C503999:SLCO1B1 protein, human; D013777:Tetrazoles; D004970:Estrone; D000069059:Atorvastatin; C558933:fimasartan; C017296:estrone sulfate