Pharmacokinetics and metabolite profiling of fimasartan, a novel antihypertensive agent, in rats

Abstract

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.

Population Pharmacokinetic Modeling of the Enterohepatic Recirculation of Fimasartan in Rats, Dogs, and Humans

“…A recent preclinical study (16) indicated that fimasartan is mainly excreted via feces; and multiple peaks in the plasma concentration-time profiles were observed both after oral and IV administration, suggesting the presence of EHC. Multiple plasma concentration peaks were also present after oral administration of fimasartan in clinical trials (17)(18)(19)(20)(21)(22), indicating that EHC impacts on human PK and potentially pharmacodynamics (PD).…”

“…The rat (16) and human (21) data have been published previously, and the dog data were generated in the present study and are presented for the first time. The data sets included in our modeling analysis are summarized in the supplement Table S1.…”

“…Sprague-Dawley rats were anesthetized with 20 mg/kg Zoletil 50® (tiletamine HCl 125 mg/5 mL+zolazepam HCl 125 mg/5 mL) and cannulated in the right jugular and femoral veins for IV injection and the right jugular vein for rats receiving oral dosing as described previously (16). Dog Studies.…”

“…Fimasartan was dissolved in distilled water, and the drug solution (0.3 and 1 mg/kg; n=6 for each group) was dosed as a bolus via the catheter followed by flushing. Blood samples of 3 mL were collected from the cephalic vein at pre-dose (within 5 min) and at 5, 10, 20, and 30 min and 1, 1.5, 2, 3, 4,6,8,12,16,20,24,48, and 72 h after IV injection.…”

“…All dogs were studied under fasting conditions. After dosing, 3 mL of blood were collected from the cephalic vein at pre-dose (within 5 min), and at 10, 20, and 30 min and 1, 1.5, 2, 3, 4,6,8,12,16,20,24,48, and 72 h. Plasma was obtained by centrifugation at 15,000×g at 4°C for 10 min and immediately frozen and stored at −70°C until analysis.…”