Pharmacokinetics and metabolite profiling of fimasartan, a novel antihypertensive agent, in rats.
1. The objectives of this study were to evaluate the pharmacokinetics and metabolism of fimasartan in rats. 2. Unlabeled fimasartan or radiolabeled [(14)C]fimasartan was dosed by intravenous injection or oral administration to rats. Concentrations of unlabeled fimasartan in the biological samples were determined by a validated LC/MS/MS assay. Total radioactivity was quantified by liquid scintillation counting and the radioactivity associated with the metabolites was analyzed by using the radiochemical detector. Metabolite identification was conducted by product ion scanning using LC/MS/MS. 3. After oral administration of [(14)C]fimasartan, total radioactivity was found primarily in feces. In bile duct cannulated rats, 58.8 ± 14.4% of the radioactive dose was excreted via bile after oral dosing. Major metabolites of fimasartan including the active metabolite, desulfo-fimasartan, were identified, yet none represented more than 7.2% of the exposure of the parent drug. Fimasartan was rapidly and extensively absorbed and had an oral bioavailability of 32.7-49.6% in rats. Fimasartan plasma concentrations showed a multi-exponential decline after oral administration. Double peaks and extended terminal half-life were observed, which was likely caused by enterohepatic recirculation. 4. These results provide better understanding on the pharmacokinetics of fimasartan and may aid further development of fimasartan analogs.
School of Pharmacy, Sungkyunkwan University , Suwon, Gyeonggi-do , South Korea .
Tae Hwan
TH
Kim
Soyoung
S
Shin
Mohammad
M
Bashir
Yong Ha
YH
Chi
Soo Heui
SH
Paik
Joo Han
JH
Lee
Hyuk Joon
HJ
Choi
Jin Ho
JH
Choi
Sun Dong
SD
Yoo
Jürgen B
JB
Bulitta
Eunsook
E
Ma
Sang Hoon
SH
Joo
Beom Soo
BS
Shin
D000284:Administration, Oral; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D001713:Biphenyl Compounds / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D002250:Carbon Radioisotopes / Q000032:analysis; D007275:Injections, Intravenous; D011743:Pyrimidines / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*; D017207:Rats, Sprague-Dawley; D013777:Tetrazoles / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics*
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D002250:Carbon Radioisotopes; D011743:Pyrimidines; D013777:Tetrazoles; C558933:fimasartan
Angiotensin II receptor blocker; fimasartan; metabolite profiling; pharmacokinetics