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.

Background This study aimed to find out the change in the rate and pattern of suicide attempts during severe acute respiratory syndrome COVID-19 pandemic period. Methods This study was a retrospective analysis of data collected as a part of an emergency room-based post-suicide management program. The data were collected through interviews and from medical records of suicide attempts, maintained in the emergency room, from January 19 to October 31, 2020, during the “COVID-19 period,” and those who attempted suicide from January 19 to October 31, 2019 “pre-COVID-19 period.” We extracted educational background, marital status, occupation, presence of domestic partner, history of mental illness, alcohol consumption, history of previous suicide attempts; suicide attempt method and location (i.e., at home or a place other than home) at the time of attempt, and whether the attempt was a mass suicide. In addition, we compared patient severity between “COVID-19 period” and “pre-COVID-19 period” using the initial KTAS (South Korean triage and acuity scale) level, consciousness level, and systolic blood pressure. In 2012, KTAS was developed through the Ministry of Health and Welfare’s research project to establish triage system in South Korea. Results The analysis of the number of suicide attempts during “pre-COVID-19 period” and “ COVID-19 period” showed that the number of suicide attempts during “COVID-19 period” (n = 440) increased compared to the “pre-COVID-19 period” (n = 400). Moreover, the method of suicide attempts during “COVID-19 period” included overdose of drugs such as hypnotics, antipsychotics, and pesticides that were already possessed by the patient increased compared to the “pre-COVID-19 period” (P < 0.05). At the time of the visit to the emergency room, high KTAS level, low level of consciousness, and low systolic blood pressure, were observed, which were significantly different between “COVID-19 period” and “pre-COVID-19 period” (P < 0.05). Conclusion With the worldwide COVID-19 virus spread, suicide rate and suicide attempts at home have significantly increased. In addition, patient severity was higher in the “COVID-19 period” than that in the “pre-COVID-19 period.” The increasing suicide attempt rate should be controlled by cooperation between the emergency room and regional organizations.

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Non-steroidal anti-inflammatory drugs (NSAIDs) are used widely to relieve pain and to decrease inflammation. Several clinical studies have reported that NSAIDs inhibit uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes. Therefore, the study evaluated the inhibitory potential of 15 NSAIDs on the activities of six UGT isoforms (i.e. UGT1A1, 1A3, 1A4, 1A6, 1A9 and 2B7) in human liver microsomes (HLMs). Among the 15 NSAIDs tested here, mefenamic acid and diclofenac inhibited all UGTs tested in this study. Piroxicam and niflumic acid inhibited UGT1A9 activity (IC50 = 73.8 μm and 0.38 μm, respectively) and naproxen selectively inhibited UGT2B7 activity (IC50 = 53.1 μm), whereas it did not inhibit the other UGTs tested (IC50 > 200 μm). Diflunisal inhibited the UGT1A1 (IC50 = 33.0 μm) and UGT1A9 (IC50 = 19.4 μm). Acetaminophen, fenoprofen, ibuprofen, ketoprofen, meloxicam, phenylbutazone, salicylic acid and sulindac showed negligible inhibitory effects on the six UGTs (IC50 > 100 μm). These results suggest that some NSAIDs have the potential to inhibit UGTs in vitro.

Obovatol, a major constituent of the leaves of Magnolia obovata Thunb, is known to inhibit nuclear factor-κB activity and arachidonic acid-induced platelet aggregation. This study was performed to identify the metabolites of obovatol in human liver microsomes. Human liver microsomes incubated with obovatol in the presence of NADPH and/or UDPGA resulted in the formation of six metabolites, M1-M6. M1 and M2 were identified as hydroxyobovatol, on the basis of liquid chromatography/tandem mass spectrometric (LC-MS/MS) analysis. M1, M2 and obovatol were further metabolized to their glucuronide conjugates, obovatol-glucuronide (M3), obovatol-diglucuronide (M4) and hydroxyobovatol-glucuronide (M5 and M6). The inhibitory potency of obovatol on eight major human P450s was also investigated in human liver microsomes. In these experiments, obovatol strongly inhibited CYP2C19-mediated S-mephenytoin hydroxylase activity with an IC(50) value of 0.8 µM, which could have implications for drug-drug interactions.