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Increased Systemic Exposure of Fimasartan, an Angiotensin II Receptor Antagonist, by Ketoconazole and Rifampicin
Author(s) -
Kim Jung Won,
Yi SoJeong,
Kim TaeEun,
Lim Kyoung Soo,
Yoon Seo Hyun,
Cho JooYoun,
Lee Min Goo,
Song ImSook,
Shin SangGoo,
Jang InJin,
Yu KyungSang
Publication year - 2013
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270011433328
Subject(s) - ketoconazole , pharmacology , medicine , pharmacokinetics , cmax , angiotensin ii , angiotensin ii receptor antagonist , angiotensin receptor , receptor , antifungal , dermatology
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.