title: Increased systemic exposure of fimasartan, an angiotensin II receptor antagonist, by ketoconazole and rifampicin.
abstract: The authors studied the effects of ketoconazole and rifampicin on the pharmacokinetics of a single dose of fimasartan (BR-A-657), a newly developed angiotensin II receptor antagonist for the treatment of hypertension, in 22 healthy participants. Ketoconazole increased the maximumplasma concentration (Cmax) and area under the plasma concentration vs time curve to infinity (AUC∞ of fimasartan by 2.47-fold (90% confidence interval [CI], 1.61-3.79) and 2.03-fold (1.56-2.64), respectively. Concomitant administration of rifampicin increased the C(max) and AUC∞ of fimasartan by 10.33-fold (90% CI, 6.74-15.81) and 4.60-fold (3.54-5.97). In vitro studies indicated that ketoconazole inhibited the uptake of fimasartan into cells expressing OATP1B1 with a K(i) of 107.7 µM, and rifampicin inhibited OAT1- and OATP1B1-mediated fimasartan transport with a K(i) of 212 µM and 12.2 µM, respectively. The systemic exposure of fimasartan was significantly increased by coadministration of ketoconazole or rifampicin in healthy volunteers. This is consistent with the in vitro results, in which fimasartan is a substrate of CYP3A and OATP1B1.
authors: Seoul National University College of Medicine and Hospital, Seoul, Korea.
authors: Jung Won
authors: JW
authors: Kim
authors: SoJeong
authors: S
authors: Yi
authors: Tae-Eun
authors: TE
authors: Kim
authors: Kyoung Soo
authors: KS
authors: Lim
authors: Seo Hyun
authors: SH
authors: Yoon
authors: Joo-Youn
authors: JY
authors: Cho
authors: Min Goo
authors: MG
authors: Lee
authors: Im-Sook
authors: IS
authors: Song
authors: Sang-Goo
authors: SG
authors: Shin
authors: In-Jin
authors: IJ
authors: Jang
authors: Kyung-Sang
authors: KS
authors: Yu
mesh_terms: D000328:Adult; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D000818:Animals; D019540:Area Under Curve; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002478:Cells, Cultured; D018592:Cross-Over Studies; D004347:Drug Interactions; D006801:Humans; D007654:Ketoconazole / Q000008:administration & dosage*; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D027362:Organic Anion Transport Protein 1 / Q000235:genetics / Q000378:metabolism; D027361:Organic Anion Transporters / Q000235:genetics / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D012293:Rifampin / Q000008:administration & dosage*; D013777:Tetrazoles / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D014982:Xenopus laevis; D055815:Young Adult
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; D027381:Liver-Specific Organic Anion Transporter 1; D027362:Organic Anion Transport Protein 1; D027361:Organic Anion Transporters; D011743:Pyrimidines; C503999:SLCO1B1 protein, human; D013777:Tetrazoles; C558933:fimasartan; D007654:Ketoconazole; D012293:Rifampin