Ideal pharmacokinetic profile of dotinurad as a selective urate reabsorption inhibitor
Dotinurad, a novel selective urate reabsorption inhibitor (SURI), has potent inhibitory effects at low doses on the uptake of urate by urate transporter 1 (URAT1, solute carrier family 22 member 12 [SLC22A12]), localized at the apical membrane of renal proximal tubular cells. This study sought to cl...
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| Veröffentlicht in: | Drug metabolism and pharmacokinetics 2020-06, Vol.35 (3), p.313-320 |
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| creator | Omura, Koichi Miyata, Kengo Kobashi, Seiichi Ito, Azusa Fushimi, Masahiko Uda, Junichiro Sasaki, Tomomitsu Iwanaga, Takashi Ohashi, Tetsuo |
| description | Dotinurad, a novel selective urate reabsorption inhibitor (SURI), has potent inhibitory effects at low doses on the uptake of urate by urate transporter 1 (URAT1, solute carrier family 22 member 12 [SLC22A12]), localized at the apical membrane of renal proximal tubular cells. This study sought to clarify the pharmacokinetic (PK) profile of dotinurad. In rats, monkeys, and humans, the apparent distribution volume (0.257, 0.205, and 0.182 L/kg, respectively) and oral clearance (0.054, 0.037, and 0.013 L·h−1·kg−1, respectively) of dotinurad were very low, whereas plasma and luminal concentrations were adequately maintained at high levels. In addition, species differences were scarcely observed with plasma protein binding of 99.4%. The main metabolite was dotinurad glucuronide (no specific metabolites in humans), and percentage excretion of unchanged dotinurad was low in all the investigated species. The risk of drug interaction with dotinurad was expected to be low, because it weakly inhibits metabolic enzymes such as cytochrome P450 (CYP). In conclusion, low-dose dotinurad exhibited excellent pharmacological effects as well as ideal PK properties as a SURI.
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| doi_str_mv | 10.1016/j.dmpk.2020.03.002 |
| format | Article |
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[Display omitted]</description><subject>Animals</subject><subject>Benzothiazoles - administration & dosage</subject><subject>Benzothiazoles - blood</subject><subject>Benzothiazoles - pharmacokinetics</subject><subject>Dose-Response Relationship, Drug</subject><subject>Dotinurad</subject><subject>Haplorhini</subject><subject>Human mass balance study</subject><subject>Humans</subject><subject>Hyperuricemia</subject><subject>Life Sciences & Biomedicine</subject><subject>Male</subject><subject>Pharmacology & Pharmacy</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Science & Technology</subject><subject>URAT1</subject><subject>Uric Acid - antagonists & inhibitors</subject><subject>Uric Acid - metabolism</subject><subject>Uricosuric agent</subject><issn>1347-4367</issn><issn>1880-0920</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>AOWDO</sourceid><sourceid>EIF</sourceid><recordid>eNqNkMFqGzEQQEVpaRy3P5BD0L3sZiStdtfQSzFJGjD00vYqtNIIy7FXiyQ75O8rY9fHkJMG8d7APEJuGNQMWHu3qe1ueq45cKhB1AD8A5mxvocKFhw-llk0XdWItrsi1yltAISQDf9MrgQXvONtNyN_nyzqLZ3WOu60Cc9-xOwNnWJwfos0OGpD9uM-akt1opom3KLJ_oC0_GWkEfWQQpyyDyP149oPPof4hXxyepvw6_mdkz8P97-XP6vVr8en5Y9VZZoF5Eob04BpmHNcMxS67Q3jg3Ct7OWig1Yz2_Ry6AYjneCyNb22nWw7yQQaFFLMCT_tNTGkFNGpKfqdjq-KgTpGUht1jKSOkRQIVSIV6fYkTfthh_ai_K9SgG8n4AWH4JLxOBq8YAAgGyFK1jJBX-j-_fTSZ31MtQz7MRf1-0nF0ujgMaqzbn0slZUN_q1D_gFe-ZpS</recordid><startdate>202006</startdate><enddate>202006</enddate><creator>Omura, Koichi</creator><creator>Miyata, Kengo</creator><creator>Kobashi, Seiichi</creator><creator>Ito, Azusa</creator><creator>Fushimi, Masahiko</creator><creator>Uda, Junichiro</creator><creator>Sasaki, Tomomitsu</creator><creator>Iwanaga, Takashi</creator><creator>Ohashi, Tetsuo</creator><general>Elsevier Ltd</general><general>Japanese Soc Study Xenobiotics</general><scope>6I.</scope><scope>AAFTH</scope><scope>AOWDO</scope><scope>BLEPL</scope><scope>DTL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><orcidid>https://orcid.org/0000-0002-8727-2732</orcidid></search><sort><creationdate>202006</creationdate><title>Ideal pharmacokinetic profile of dotinurad as a selective urate reabsorption inhibitor</title><author>Omura, Koichi ; Miyata, Kengo ; Kobashi, Seiichi ; Ito, Azusa ; Fushimi, Masahiko ; Uda, Junichiro ; Sasaki, Tomomitsu ; Iwanaga, Takashi ; Ohashi, Tetsuo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c490t-acc40c41ff2a1e3a68c12b3f65859706a1d485b7bc5f3256c8ad7567513ece353</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><topic>Animals</topic><topic>Benzothiazoles - administration & dosage</topic><topic>Benzothiazoles - blood</topic><topic>Benzothiazoles - pharmacokinetics</topic><topic>Dose-Response Relationship, Drug</topic><topic>Dotinurad</topic><topic>Haplorhini</topic><topic>Human mass balance study</topic><topic>Humans</topic><topic>Hyperuricemia</topic><topic>Life Sciences & Biomedicine</topic><topic>Male</topic><topic>Pharmacology & Pharmacy</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Science & Technology</topic><topic>URAT1</topic><topic>Uric Acid - antagonists & inhibitors</topic><topic>Uric Acid - metabolism</topic><topic>Uricosuric agent</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Omura, Koichi</creatorcontrib><creatorcontrib>Miyata, Kengo</creatorcontrib><creatorcontrib>Kobashi, Seiichi</creatorcontrib><creatorcontrib>Ito, Azusa</creatorcontrib><creatorcontrib>Fushimi, Masahiko</creatorcontrib><creatorcontrib>Uda, Junichiro</creatorcontrib><creatorcontrib>Sasaki, Tomomitsu</creatorcontrib><creatorcontrib>Iwanaga, Takashi</creatorcontrib><creatorcontrib>Ohashi, Tetsuo</creatorcontrib><collection>ScienceDirect Open Access Titles</collection><collection>Elsevier:ScienceDirect:Open Access</collection><collection>Web of Science - Science Citation Index Expanded - 2020</collection><collection>Web of Science Core Collection</collection><collection>Science Citation Index Expanded</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><jtitle>Drug metabolism and pharmacokinetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Omura, Koichi</au><au>Miyata, Kengo</au><au>Kobashi, Seiichi</au><au>Ito, Azusa</au><au>Fushimi, Masahiko</au><au>Uda, Junichiro</au><au>Sasaki, Tomomitsu</au><au>Iwanaga, Takashi</au><au>Ohashi, Tetsuo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Ideal pharmacokinetic profile of dotinurad as a selective urate reabsorption inhibitor</atitle><jtitle>Drug metabolism and pharmacokinetics</jtitle><stitle>DRUG METAB PHARMACOK</stitle><addtitle>Drug Metab Pharmacokinet</addtitle><date>2020-06</date><risdate>2020</risdate><volume>35</volume><issue>3</issue><spage>313</spage><epage>320</epage><pages>313-320</pages><issn>1347-4367</issn><eissn>1880-0920</eissn><abstract>Dotinurad, a novel selective urate reabsorption inhibitor (SURI), has potent inhibitory effects at low doses on the uptake of urate by urate transporter 1 (URAT1, solute carrier family 22 member 12 [SLC22A12]), localized at the apical membrane of renal proximal tubular cells. This study sought to clarify the pharmacokinetic (PK) profile of dotinurad. In rats, monkeys, and humans, the apparent distribution volume (0.257, 0.205, and 0.182 L/kg, respectively) and oral clearance (0.054, 0.037, and 0.013 L·h−1·kg−1, respectively) of dotinurad were very low, whereas plasma and luminal concentrations were adequately maintained at high levels. In addition, species differences were scarcely observed with plasma protein binding of 99.4%. The main metabolite was dotinurad glucuronide (no specific metabolites in humans), and percentage excretion of unchanged dotinurad was low in all the investigated species. The risk of drug interaction with dotinurad was expected to be low, because it weakly inhibits metabolic enzymes such as cytochrome P450 (CYP). In conclusion, low-dose dotinurad exhibited excellent pharmacological effects as well as ideal PK properties as a SURI.
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| subjects | Animals Benzothiazoles - administration & dosage Benzothiazoles - blood Benzothiazoles - pharmacokinetics Dose-Response Relationship, Drug Dotinurad Haplorhini Human mass balance study Humans Hyperuricemia Life Sciences & Biomedicine Male Pharmacology & Pharmacy Rats Rats, Sprague-Dawley Science & Technology URAT1 Uric Acid - antagonists & inhibitors Uric Acid - metabolism Uricosuric agent |
| title | Ideal pharmacokinetic profile of dotinurad as a selective urate reabsorption inhibitor |
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