Characterization of fimasartan metabolites in human liver microsomes and human plasma

Abstract

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.

Fimasartan: A New Angiotensin Receptor Blocker

“…Major metabolic pathways are oxidative desulfuration, N-glucuronidation, mono-oxygenation of pyrimidinone, hydroxylation of the n-butyl group, and de-N-dimethylation [7]. Among these, mono-oxygenation is the major metabolic reaction and the prominent metabolites were fimasartan S-oxide and fimasartan N-glucuronide [15]. Pharmacological profiles of fimasartan are summarized in Table 1.…”

The Rho-associated kinase inhibitor fasudil can replace Y-27632 for use in human pluripotent stem cell research

“…HPLC was performed as previously described [22]. Briefly, samples (50 uL) were precipitated with 150 μL of cold acetonitrile containing carbamazepine as internal standard (CBZ, 10 ng/ ml) and agitated with a vortex mixer before centrifugation at 3400 rpm and 4˚C for 20 minutes.…”

Mimicking of Phase I Metabolism Reactions of Molindone by HLM and Photocatalytic Methods with the Use of UHPLC-MS/MS

“…The activity that the liver shows in the metabolism of medicines has become the basis for developing an in vitro assay for determining drug metabolism [21]. The human liver microsomes (HLMs) used for this purpose provide satisfactory results with reference to drug molecules undergoing the hepatic pathway [22][23][24]. In spite of its unequivocal usefulness in drug metabolism studies, this approach also reflects minor drawbacks.…”