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      Dotinurad: a clinical pharmacokinetic study of a novel, selective urate reabsorption inhibitor in subjects with hepatic impairment

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          Abstract

          Background

          Dotinurad is a novel, selective urate reabsorption inhibitor, which reduces serum uric acid levels by inhibiting the urate transporter 1 (URAT1). We compared the pharmacokinetics (PK), pharmacodynamics (PD), and safety of dotinurad in subjects with hepatic impairment and normal hepatic function.

          Methods

          This was a multicenter, open-label, single dose study. A total of 24 subjects were divided into four groups: the normal hepatic function group and the mild, moderate, and severe hepatic impairment groups. The primary endpoints were changes in plasma dotinurad levels and PK parameters.

          Results

          The geometric mean ratio of the maximum plasma concentration ( C max) [two-sided 90% confidence interval (CI)] of dotinurad in in the mild, moderate, and severe hepatic impairment groups relative to that in the normal hepatic function group was 0.840 (0.674–1.047), 0.798 (0.653–0.976), and 0.747 (0.570–0.979), respectively, showing a lower C max in the moderate and severe hepatic impairment groups. Following adjustment for body weight, only the moderate hepatic impairment group had a lower C max than the normal hepatic function group. No meaningful differences in other PK parameters were observed between the groups. Regarding the PD of dotinurad, the changes in serum uric acid levels after dosing were similar in all groups. As for safety, no noteworthy concerns were raised in relation to any group.

          Conclusion

          The study revealed no clinically meaningful influence of hepatic impairment on the PK, PD, or safety of dotinurad. These findings indicate possibility that dotinurad can be used without dose adjustment in patients with hepatic impairment.

          Electronic supplementary material

          The online version of this article (10.1007/s10157-019-01816-4) contains supplementary material, which is available to authorized users.

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          Most cited references 7

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          Hepatic injury caused by benzbromarone.

          This case study describes a woman who developed a predominantly hepatocellular injury, approximately 3 months after starting treatment with 100 mg benzbromarone daily. She had also taken 250 mg methyldopa daily for several years. Infections with hepatitis A and B were excluded serologically, no autoantibodies were demonstrated, and ultrasonography and endoscopic retrograde cholangiopancreatography did not show extrahepatic obstruction. The patient recovered after discontinuation of both drugs. Two years later, readministration of benzbromarone was followed by a relapse. Later, methyldopa was used without problems. We conclude that hepatic injury in this patient was caused by benzbromarone.
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            Conjugation pathways in liver disease.

            1. The activities of microsomal glucuronyltransferase and thiomethyltransferase, and those of cytosolic sulphotransferase, acetyltransferase, glutathione transferase and thiomethyltransferase were measured in abnormal (cirrhosis and chronic hepatitis) and normal livers. 2. Glucuronyltransferase and sulphotransferase were investigated with 2-naphthol and ethinyloestradiol as substrates. p-Aminobenzoic acid, benzo(a)pyrene-4,5-epoxide and 2-mercaptoethanol were the substrates of acetyltransferase, glutathione transferase and thiomethyltransferase, respectively. 3. Enzyme activities are expressed as nmol min-1 incubation mg-1 protein and the averages (+/- s.d.) are given. With 2-naphthol as substrate, the glucuronyltransferase activity was 6.55 +/- 4.10 (abnormal liver, n = 33) and 7.81 +/- 4.02 (normal liver, n = 26) (NS); whereas sulphotransferase activity was 0.28 +/- 0.18 (abnormal liver, n = 35) and 0.68 +/- 0.43 (normal liver, n = 26) (P less than 0.01). Glucuronyltransferase activity towards ethinyloestradiol was 102.5 +/- 56.9 (abnormal liver, n = 30) and 107 +/- 59.9 (normal liver, n = 26) (NS), whereas sulphotransferase activity was 57.2 +/- 36.0 (abnormal liver, n = 35) and 122 +/- 67.6 (normal liver, n = 28) (P less than 0.01). Acetyltransferase activity was 0.84 +/- 0.83 (abnormal liver, n = 35) and 3.84 +/- 1.65 (normal liver, n = 26) (P less than 0.01). Glutathione transferase activity was 0.83 +/- 0.68 (abnormal liver, n = 35) and 2.90 +/- 1.59 (normal liver, n = 25) (P less than 0.01) and thiomethyltransferase activity was 1.00 +/- 0.69 (abnormal liver, n = 34) and 3.99 +/- 1.49 (normal liver, n = 25) (P less than 0.01). 4. Liver disease lowers the activities towards the substrates studied of sulphotransferase, acetyltransferase, glutathionetransferase and thiomethyltransferase but not that of glucuronyltransferase.(ABSTRACT TRUNCATED AT 250 WORDS)
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              Is hyperuricemia increasing? Focusing on gender difference

               M Tomita,  S. MIZUNO,  S Mizuno (2006)
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                Author and article information

                Contributors
                kuma-guy@za2.so-net.ne.jp
                Journal
                Clin Exp Nephrol
                Clin. Exp. Nephrol
                Clinical and Experimental Nephrology
                Springer Singapore (Singapore )
                1342-1751
                1437-7799
                23 November 2019
                23 November 2019
                2020
                : 24
                : Suppl 1
                : 25-35
                Affiliations
                [1 ]GRID grid.410786.c, ISNI 0000 0000 9206 2938, Kitasato University School of Medicine, ; 1-15-1, Kitasato, Minami-ku, Sagamihara, Kanagawa 252-0374 Japan
                [2 ]GRID grid.412812.c, ISNI 0000 0004 0443 9643, Showa University Hospital, ; 1-5-8, Hatanodai, Shinagawa-ku, Tokyo, 142-8666 Japan
                [3 ]P-One Clinic, Keikokai Medical Corporation, 8-1 Yokamachi, Hachioji, Tokyo 192-0071 Japan
                [4 ]GRID grid.410714.7, ISNI 0000 0000 8864 3422, Digestive Disease Center, , Showa University Koto Toyosu Hospital, ; 5-1-38, Toyosu, Koto-ku, Tokyo, 135-8577 Japan
                [5 ]GRID grid.412808.7, ISNI 0000 0004 1764 9041, Showa University Fujigaoka Hospital, ; 1-30, Fujigaoka, Aoba-ku, Yokohama, Kanagawa 227-8501 Japan
                [6 ]Kurume Clinical Pharmacology Clinic, 67, Asahimachi, Kurume, Fukuoka 830-0011 Japan
                [7 ]GRID grid.467457.3, ISNI 0000 0004 1800 5387, Clinical Research Department, , Mochida Pharmaceutical Co., Ltd, ; 1-22 Yotsuya, Shinjuku-ku, Tokyo, 160-0004 Japan
                Article
                1816
                10.1007/s10157-019-01816-4
                7066095
                31760530
                © The Author(s) 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

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                © Japanese Society of Nephrology 2020

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