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Increased systemic exposure of fimasartan, an angiotensin II receptor antagonist, by ketoconazole and rifampicin

 Jung Won Kim  ;  SoJeong Yi  ;  Tae-Eun Kim  ;  Kyoung Soo Lim  ;  Seo Hyun Yoon  ;  Joo-Youn Cho  ;  Min Goo Lee  ;  Im-Sook Song  ;  Sang-Goo Shin  ;  In-Jin Jang  ;  Kyung-Sang Yu 
 Journal of Clinical Pharmacology, Vol.53(1) : 75-81, 2013 
Journal Title
 Journal of Clinical Pharmacology 
Issue Date
Adult ; Angiotensin II Type 1 Receptor Blockers/administration & dosage ; Angiotensin II Type 1 Receptor Blockers/blood ; Angiotensin II Type 1 Receptor Blockers/pharmacokinetics* ; Animals ; Area Under Curve ; Biphenyl Compounds/administration & dosage ; Biphenyl Compounds/blood ; Biphenyl Compounds/pharmacokinetics* ; Cells, Cultured ; Cross-Over Studies ; Drug Interactions ; Humans ; Ketoconazole/administration & dosage* ; Male Oocytes/drug effects ; Oocytes/metabolism ; Organic Anion Transport Protein 1/genetics ; Organic Anion Transport Protein 1/metabolism ; Organic Anion Transporters/genetics ; Organic Anion Transporters/metabolism ; Pyrimidines/administration & dosage ; Pyrimidines/blood ; Pyrimidines/pharmacokinetics* ; Rifampin/administration & dosage* ; Solute Carrier Organic Anion Transporter Family Member 1b1 ; Tetrazoles/administration & dosage ; Tetrazoles/blood ; Tetrazoles/pharmacokinetics* ; Xenopus laevis ; Young Adult
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.
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1. College of Medicine (의과대학) > Dept. of Pharmacology (약리학교실) > 1. Journal Papers
Yonsei Authors
Lee, Min Goo(이민구) ORCID logo https://orcid.org/0000-0001-7436-012X
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