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Ansan, South Korea

Lee J.-Y.,Chungnam National University | Choi Y.J.,Chungnam National University | Oh S.J.,Korea Research Institute of Bioscience and Biotechnology | Chi Y.H.,Boryung Pharm. Co. | And 8 more authors.
Xenobiotica | Year: 2016

1. The metabolites of fimasartan (FMS), a new angiotensin II receptor antagonist, were characterized in human liver microsomes (HLM) and human subjects.2. We developed a method for a simultaneous quantitative and qualitative analysis using predictive multiple reaction monitoring information-dependent acquisition-enhanced product ion scanning. To characterize metabolic reactions, FMS metabolites were analyzed using quadrupole-time of flight mass spectrometer in full-scan mode.3. The structures of metabolites were confirmed by comparison of chromatographic retention times and mass spectra with those of authentic metabolite standards.4. In the cofactor-dependent microsomal metabolism study, the half-lives of FMS were 56.7, 247.9 and 53.3 min in the presence of NADPH, UDPGA and NADPH + UDPGA, respectively.5. The main metabolic routes in HLM were S-oxidation, oxidative desulfuration, n-butyl hydroxylation and N-glucuronidation.6. In humans orally administered with 120 mg FMS daily for 7 days, the prominent metabolites were FMS S-oxide and FMS N-glucuronide in the 0-8-h pooled plasma sample of each subject.7. This study characterizes, for the first time, the metabolites of FMS in humans to provide information for its safe use in clinical medicine. © 2015 Informa UK Ltd. All rights reserved.

Jeong E.-S.,Inje University | Kim Y.-W.,Inje University | Kim H.-J.,Inje University | Shin H.-J.,Inje University | And 5 more authors.
Xenobiotica | Year: 2014

1.Fimasartan is an angiotensin receptor II antagonist used to treat patients with hypertension. This drug is mainly excreted into bile as either the parent compound or a glucuronide conjugate. In this study, we examined the glucuronidation of fimasartan and characterized the UDP-glucuronosyltransferases (UGTs) responsible for the glucuronidation. 2.Only one type of fimasartan glucuronide was observed after incubation with pooled human liver microsomes (HLMs) and was identified as an N2-glucuronide based on comparison with an authentic standard. 3.Among the 12 UGT isoforms tested, UGT1A1, UGT1A3 and UGT2B7 showed catalytic activity toward fimasartan glucuronidation. The intrinsic clearance (CLint) of UGT1A3 was 68.5- and 21.4-fold higher than that of UGT1A1 and UGT2B7, respectively, and the estimated relative contribution of UGT1A3 in human liver was 94.1%. Both chemical inhibition and correlation studies demonstrated that fimasartan glucuronidation activity in HLMs was significantly related with UGT1A3 activity. Fimasartan glucuronide was identified as a substrate for P-glycoprotein (Pgp) and breast cancer response protein (BCRP). 4.These findings collectively indicate that UGT1A3 is the major UGT isoform responsible for the glucuronidation of fimasartan, and this glucuronide is excreted from hepatocytes via MDR1 and BCRP. © 2015 Informa UK Ltd. All rights reserved: reproduction in whole or part not permitted.

Yeong Park J.,Kyung Hee University | Woo Choi H.,Kyung Hee University | Li Choi D.,Kyung Hee University | Jeong Jang S.,Kyung Hee University | And 6 more authors.
Bulletin of the Korean Chemical Society | Year: 2013

Two piperazine-containing 3,4-dihyroquinazolines (BK10007S/8S) have been synthesized, based on our previous work on the synthesis and antitumoral activity of 3,4-dihyroquinazolines. After evaluating them for T-type calcium channel blocking effect and in vitro anti-cancer effect, they were profiled for acute and repeat dose toxicity (40 mg/kg, 2 weeks) to BALB/c mice. BK10007S/8S were further in vivo evaluated against human pancreatic MIA PaCa-2 carcinoma in BALB/cnu/nu nude mice, which exhibited 54 and 61% tumor growth inhibition through 57-day oral administration of 2 mg/kg of body weight, respectively.

Kim T.H.,Sungkyunkwan University | Shin S.,Wonkwang University | Bashir M.,Covance Laboratories Inc. | Chi Y.H.,Boryung Pharm. Co. | And 9 more authors.
Xenobiotica | Year: 2014

The objectives of this study were to evaluate the pharmacokinetics and metabolism of fimasartan in rats.

Chi Y.H.,Boryung Pharm. Co. | Lee H.,University of California at San Francisco | Lee H.,University of Washington | Paik S.H.,Boryung Pharm. Co. | And 5 more authors.
American Journal of Cardiovascular Drugs | Year: 2011

Background and Objectives: Fimasartan (BR-A-657) is a novel, non-peptide angiotensin II receptor antagonist with a selective type I receptor blockade effect. Two first-in-human studies investigated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of fimasartan. Methods: Fasted single oral tablet doses of fimasartan 20-480 mg or placebo were administered to 40 healthy male subjects (aged 19-54 years) in a double-blind, randomized, sequential-group design. Subjects receiving fimasartan 240mg also received the same treatment in the fed state after an interval of 7 days. In another study, oral tablet doses of fimasartan 120 and 360mg or placebo were given once daily for 7 days to groups of eight fasted healthy male subjects (aged 20-55 years) in a double-blind, randomized, sequential-group design. Safety and tolerability were assessed. The PK and PD of fimasartan were also evaluated and compared for the different doses. Results: Fimasartan was safe and well tolerated, but with an increased incidence of low BP and postural dizziness for the 360mg dose after repeated administration. Fimasartan produced increases in plasma renin activity, angiotensin I and II, which were not dose dependent. Maximal increases occurred between 6 and 8 hours post-dose, lasting up to 48 hours. Fimasartan was absorbed rapidly after all doses and had a multiphasic distribution. Two peaks in the plasma concentration-time profile were observed in most subjects. Steady state was achieved after three doses, and accumulation was minimal after repeated doses for 7 days (24-30%). The effective half-life ranged from 9.84 to 13.2 hours. The systemic exposure of fimasartan was dose proportional, and no marked food effect was noted after administration of 240mg in the fed state. Urinary excretion of fimasartan was very low (1.74-2.51%), suggesting non-renal elimination. Conclusion: Fimasartan had a good safety profile and was well tolerated after fasted single oral doses of 20-480 mg, a fed single oral dose of 240 mg, and fasted repeated oral doses of 120 and 360mg in healthy subjects. In addition, the PK and PD of fimasartan in this population were well characterized. Further studies are needed to evaluate the safety, efficacy, and dose-response relationship of fimasartan in patients. with hypertension. © 2011 Adis Data Information BV. All rights reserved.

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