The Effect of the Newly Developed Angiotensin Receptor II Antagonist Fimasartan on the Pharmacokinetics of Atorvastatin in Relation to OATP1B1 in Healthy Male Volunteers

Abstract

We showed that fimasartan raised plasma atorvastatin concentrations. In vitro tests suggested that this effect may have been mediated by fimasartan inhibition of organic anion-transporting polypeptide 1B1.

Decreased potency of fimasartan in liver cirrhosis was quantified using mixed-effects analysis

“…Fimasartan is eliminated mostly to feces via biliary excretion by organic anion-transporting polypeptides, it is also metabolized primarily by CYP3A4. [4,5,10] Only two subjects in the group with mild hepatic impairment were diagnosed with liver cirrhosis, by contrast, all of the subjects in the group with moderate hepatic impairment group were patients with chronic liver cirrhosis.…”

“…[3] The absolute bioavailability of orally administered fimasartan in healthy subjects is 18.6%, [4] and its protein binding is about 96%. [5] Most of the circulating fimasartan in plasma is in the parent form, although fimasartan is catabolized by multiple cytochrome P450s (CYP), mainly CYP3A4, UDP-glucuronosyltransferases, and other enzymes. [6] The urinary excretion of unchanged fimasartan is <3% over the first 24 h after administration, and it is mostly excreted into the bile as either parent or in a glucuronide conjugated form.…”

Fimasartan: A New Angiotensin Receptor Blocker

“…Fecal elimination and biliary excretion are the predominant elimination pathways of fimasartan and urinary excretion was found to be less than 3 % 24 h after administration [2]. During biotransformation, fimasartan is primarily catabolized by cytochrome P450 (CYP) 3A; however, other CYP and UDP-glucuronosyl transferase (UGT) enzymes are involved with at least 20 % of fimasartan metabolism [3,13,14]. Major metabolic pathways are oxidative desulfuration, N-glucuronidation, mono-oxygenation of pyrimidinone, hydroxylation of the n-butyl group, and de-N-dimethylation [7].…”

“…Pharmacokinetic studies of patients with moderate hepatic impairments reported that the bioavailability of fimasartan was 5-fold higher than that of healthy controls, suggesting reduced uptake of fimasartan by organic aniontransporting polypeptides (OATPs) into the liver [14,16]. Although the renal elimination of fimasartan is less than 3 %, a study of patients with renal impairments (estimated glomerular filtration rate \30 mL/min/1.73 m 2 ) found the C max and AUC was increased by 1.87-and 1.73-fold, respectively, compared with healthy volunteers [17].…”

“…However, co-administration of fimasartan with rifampin, a known potent OATP inhibitor, increases the C max and AUC from time zero to infinity by 10.3-and 4.6-fold, respectively [23]. Conversely, fimasartan raised plasma atorvastatin concentrations due to inhibition of OATP1B1 [14]. Lastly, ketoconazole, a potent inhibitor of CYP3A4, increased the AUC of fimasartan by 2-fold compared with that of fimasartan alone [23].…”