{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,30]],"date-time":"2026-08-30T03:10:01Z","timestamp":1788059401367,"version":"build-2784847793"},"reference-count":27,"publisher":"SAGE Publications","issue":"6","license":[{"start":{"date-parts":[[2004,12,1]],"date-time":"2004-12-01T00:00:00Z","timestamp":1101859200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"},{"start":{"date-parts":[[2004,12,1]],"date-time":"2004-12-01T00:00:00Z","timestamp":1101859200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Antivir Chem Chemother"],"published-print":{"date-parts":[[2004,12]]},"abstract":"<jats:p>Adefovir dipivoxil (Hepsera\u2122), a first-line therapy for chronic hepatitis B, is an esterase-activated prodrug of PMEA. Dose-limiting nephrotoxicity necessitates suboptimal dosing at 10 mg\/day. Remofovir mesylate (MB06866Q) (Hepavir B) is a CYP3A4-activated prodrug of PMEA based on the HepDirect\u2122 technology that targets PMEA to the liver. In a whole body autoradiography study in rats after oral dosing (30 mg\/kg) of [<jats:sup>14<\/jats:sup>C]adefovir dipivoxil or [<jats:sup>14<\/jats:sup>C]remofovir mesylate, remofovir yielded 15 times higher concentrations of radioactivity in the liver than adefovir dipivoxil, but only one-third of the concentrations in the kidney. After oral dosing (4 mg\/kg) of the same radiolabelled agents in cynomolgus monkeys, remofovir mesylate yielded 60 times higher levels of total radioactivity in the liver, but only two-thirds of total radioactivity levels in the kidney. Thus, remofovir mesylate may provide better efficacy and reduced nephrotoxicity. In portal vein-cannulated rats (30 mg\/kg) after a single oral dose of [<jats:sup>14<\/jats:sup>C]adefovir dipivoxil or [<jats:sup>14<\/jats:sup>C]remofovir mesylate, no PMEA was detectable in rat portal plasma early after dosing, indicating that intestinal CYP3A4 does not play a role in conversion of remofovir mesylate to PMEA. The portal\/systemic extraction ratio was quite high in both models, suggesting good liver-targeting properties. Portal and systemic remofovir\/PMEA ratio indicates that the liver is the site of conversion of remofovir to PMEA. 28-Day toxicity studies demonstrated renal toxicity in rats at doses of 100 mg\/kg or higher with no safety concerns at 30 mg\/kg and acceptable safety in monkeys at doses up to 60 mg\/kg. Thus, in rats and non-human primates, remofovir mesylate has liver-targeting properties and is safer than adefovir dipivoxil.<\/jats:p>","DOI":"10.1177\/095632020401500603","type":"journal-article","created":{"date-parts":[[2015,3,16]],"date-time":"2015-03-16T17:01:37Z","timestamp":1426525297000},"page":"307-317","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":15,"title":["Remofovir Mesylate: A Prodrug of PMEA with Improved Liver-Targeting and Safety in Rats and Monkeys"],"prefix":"10.1177","volume":"15","author":[{"given":"Chin-Chung","family":"Lin","sequence":"first","affiliation":[{"name":"Valeant Pharmaceuticals International, Costa Mesa, Calif., USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li-Tain","family":"Yeh","sequence":"additional","affiliation":[{"name":"Valeant Pharmaceuticals International, Costa Mesa, Calif., USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Domenico","family":"Vitarella","sequence":"additional","affiliation":[{"name":"Valeant Pharmaceuticals International, Costa Mesa, Calif., USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhi","family":"Hong","sequence":"additional","affiliation":[{"name":"Valeant Pharmaceuticals International, Costa Mesa, Calif., USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark D","family":"Erion","sequence":"additional","affiliation":[{"name":"Metabasis Therapeutics, Inc., San Diego, Calif., USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2004,12,1]]},"reference":[{"key":"bibr1-095632020401500603","doi-asserted-by":"publisher","DOI":"10.1023\/A:1012155717819"},{"key":"bibr2-095632020401500603","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.88.4.1499"},{"key":"bibr3-095632020401500603","doi-asserted-by":"publisher","DOI":"10.1086\/514057"},{"key":"bibr4-095632020401500603","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.1.117"},{"key":"bibr5-095632020401500603","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.38.2.365"},{"key":"bibr6-095632020401500603","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.11.2401"},{"key":"bibr7-095632020401500603","doi-asserted-by":"publisher","DOI":"10.1080\/00498250110112006"},{"key":"bibr8-095632020401500603","first-page":"301A","volume":"36","author":"Erion MD","year":"2002","journal-title":"Hepatology"},{"key":"bibr9-095632020401500603","doi-asserted-by":"publisher","DOI":"10.1021\/ja031818y"},{"key":"bibr10-095632020401500603","doi-asserted-by":"crossref","unstructured":"Erion MD, van Poelje PD, MacKenna DA, Colby TJ, Montag A, Fujitaki JM, Linemeyer DL & Bullough DA (2004b) Liver targeted drug delivery using HepDirect\u2122 prodrugs. 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