{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T04:42:15Z","timestamp":1790743335366,"version":"4.1.0"},"reference-count":48,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2019,4,8]],"date-time":"2019-04-08T00:00:00Z","timestamp":1554681600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100004319","name":"Pfizer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100004319","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2019,10]]},"abstract":"<jats:p><jats:styled-content style=\"fixed-case\">PF<\/jats:styled-content>\u201004991532 ((S)\u20106\u2010(3\u2010Cyclopentyl\u20102\u2010(4\u2010(trifluoromethyl)\u20101H\u2010imidazol\u20101\u2010yl) propanamido) nicotinic acid) is a glucokinase activator designed to achieve hepato\u2010selectivity via organic anion\u2010transporting polypeptides (<jats:styled-content style=\"fixed-case\">OATP<\/jats:styled-content><jats:bold>)<\/jats:bold>s, so as to minimize systemic hypoglycemic effects. This study investigated the effect of <jats:styled-content style=\"fixed-case\">OATP<\/jats:styled-content>1B1\/1B3 inhibition and renal impairment on <jats:styled-content style=\"fixed-case\">PF<\/jats:styled-content>\u201004991532 oral pharmacokinetics. Cyclosporine (600\u00a0mg single dose) increased mean area under the plasma curve (<jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content>) of <jats:styled-content style=\"fixed-case\">PF<\/jats:styled-content>\u201004991532 by approximately threefold in healthy subjects. In a renal impairment study, <jats:styled-content style=\"fixed-case\">PF<\/jats:styled-content>\u201004991532 <jats:styled-content style=\"fixed-case\">AUC<\/jats:styled-content> values were ~\u00a02.3\u2010fold greater in subjects with mild, moderate, and severe kidney dysfunction, compared with healthy subjects. Physiologically\u2010based pharmacokinetic (<jats:styled-content style=\"fixed-case\">PBPK<\/jats:styled-content><jats:bold>)<\/jats:bold> model parameterizing hepatic and renal transporter\u2010mediated disposition based on <jats:italic>in vitro<\/jats:italic> inputs, and verified using first\u2010in\u2010human data, indicated the key role of <jats:styled-content style=\"fixed-case\">OATP<\/jats:styled-content>\u2010mediated hepatic uptake in the systematic and target\u2010tissue exposure of <jats:styled-content style=\"fixed-case\">PF<\/jats:styled-content>\u201004991532. Mechanistic evaluation of the clinical data suggest reduced hepatic <jats:styled-content style=\"fixed-case\">OATP<\/jats:styled-content>s (~\u00a035%) and renal organic anion transporter (<jats:styled-content style=\"fixed-case\">OAT<\/jats:styled-content><jats:bold>)<\/jats:bold>3 (80\u201390%) function with renal impairment. This study illustrates the adequacy and utility of the <jats:styled-content style=\"fixed-case\">PBPK<\/jats:styled-content> approach in assessing the impact of drug interactions and kidney dysfunction on transporter\u2010mediated disposition.<\/jats:p>","DOI":"10.1002\/cpt.1419","type":"journal-article","created":{"date-parts":[[2019,3,28]],"date-time":"2019-03-28T10:42:49Z","timestamp":1553769769000},"page":"792-802","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Effect of Hepatic Organic Anion\u2010Transporting Polypeptide 1B Inhibition and Chronic Kidney Disease on the Pharmacokinetics of a Liver\u2010Targeted Glucokinase Activator: A Model\u2010Based Evaluation"],"prefix":"10.1111","volume":"106","author":[{"given":"Arthur","family":"Bergman","sequence":"first","affiliation":[{"name":"Clinical Pharmacology Worldwide Research and Development Pfizer Inc.  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi\u2010an","family":"Bi","sequence":"additional","affiliation":[{"name":"Medicine Design Worldwide Research and Development Pfizer Inc.  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumathy","family":"Mathialagan","sequence":"additional","affiliation":[{"name":"Medicine Design Worldwide Research and Development Pfizer Inc.  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John","family":"Litchfield","sequence":"additional","affiliation":[{"name":"Worldwide Research and Development Pfizer Inc.  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Kazierad","sequence":"additional","affiliation":[{"name":"Worldwide Research and Development Pfizer Inc.  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey A.","family":"Pfefferkorn","sequence":"additional","affiliation":[{"name":"Worldwide Research and Development Pfizer Inc.  Cambridge Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9541-6329","authenticated-orcid":false,"given":"Manthena V.S.","family":"Varma","sequence":"additional","affiliation":[{"name":"Medicine Design Worldwide Research and Development Pfizer Inc.  Groton Connecticut USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,4,8]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.2337\/diabetes.47.3.307"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20080595"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-008-8322-9"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm100039a"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm8003202"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1039\/c1md00092f"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1084073"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2012.11.007"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1517\/13543776.2011.542413"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm900839k"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1021\/jm2014887"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2009.10.020"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756-0500-7-415"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.116.074294"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-012-0792-7"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.117.080044"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-015-1749-4"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.106.011866"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.3810\/pgm.2012.07.2579"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.114.061218"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-012-0918-y"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.108.146647"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2011.142"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1080\/00498250601188808"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2008.59"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2013.399"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.337"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.807"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-005-1709-6"},{"key":"e_1_2_10_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.1205"},{"key":"e_1_2_10_31_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-013-0117-y"},{"key":"e_1_2_10_32_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-014-0156-z"},{"key":"e_1_2_10_33_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdd.1823"},{"key":"e_1_2_10_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.437"},{"key":"e_1_2_10_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2013.85"},{"key":"e_1_2_10_36_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2013.78"},{"key":"e_1_2_10_37_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.molpharmaceut.7b01108"},{"key":"e_1_2_10_38_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.117.245951"},{"key":"e_1_2_10_39_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.114.215970"},{"key":"e_1_2_10_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.xphs.2017.04.043"},{"key":"e_1_2_10_41_1","doi-asserted-by":"publisher","DOI":"10.1208\/s12248-014-9614-7"},{"key":"e_1_2_10_42_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.115.064303"},{"key":"e_1_2_10_43_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.520"},{"key":"e_1_2_10_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-013-0097-y"},{"key":"e_1_2_10_45_1","doi-asserted-by":"publisher","DOI":"10.1002\/jps.20502"},{"key":"e_1_2_10_46_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11095-012-0956-5"},{"key":"e_1_2_10_47_1","doi-asserted-by":"publisher","DOI":"10.1124\/dmd.110.032268"},{"key":"e_1_2_10_48_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-014-0188-4"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fcpt.1419","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.1419","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.1419","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.1419","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,7]],"date-time":"2023-11-07T13:30:18Z","timestamp":1699363818000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.1419"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,8]]},"references-count":48,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2019,10]]}},"alternative-id":["10.1002\/cpt.1419"],"URL":"https:\/\/doi.org\/10.1002\/cpt.1419","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,8]]},"assertion":[{"value":"2018-12-17","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-02-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2019-04-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}