{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T01:57:04Z","timestamp":1791079024225,"version":"4.1.0"},"reference-count":20,"publisher":"American Society for Microbiology","issue":"7","license":[{"start":{"date-parts":[[1998,7,1]],"date-time":"1998-07-01T00:00:00Z","timestamp":899251200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["Antimicrob Agents Chemother"],"published-print":{"date-parts":[[1998,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    To overcome the low oral bioavailability of the highly potent and selective antiretroviral agent (\n                    <jats:italic>R<\/jats:italic>\n                    )-9-(2-phosphonylmethoxypropyl)adenine (PMPA), a new lipophilic ester derivative, i.e., the bis(isopropyloxycarbonyloxymethyl)-ester [bis(POC)-PMPA], was prepared. The usefulness of bis(POC)-PMPA as an oral prodrug for PMPA was investigated in the intestinal mucosa Caco-2 cell monolayer model. The total transport of bis(POC)-PMPA was 2.7%, whereas it was less than 0.1% for PMPA. Bis(POC)-PMPA was considerably metabolized inside the epithelial cells, since the majority of the compound was recovered after transport in the form of the monoester metabolite [mono(POC)-PMPA]. In contrast, bis(POC)-PMPA was relatively resistant to degradation at the luminal side of the Caco-2 cells. Pharmacokinetic studies with mice showed that the oral bioavailability of bis(POC)-PMPA (calculated from the curves of the concentration of free PMPA in plasma) was 20%. Neither bis(POC)-PMPA nor mono(POC)-PMPA could be recovered in plasma, suggesting the efficient release of the active drug PMPA after oral administration of bis(POC)-PMPA. Severe combined immunodeficient (SCID) mice infected with Moloney murine sarcoma virus (MSV) and treated orally with bis(POC)-PMPA for 5 or 10 days (dosages, 50, 100, or 200 mg of PMPA equivalent per kg of body weight per day) showed a significant delay in MSV-induced tumor appearance and tumor-associated death. The antiviral efficacy of oral bis(POC)-PMPA was related to the dosage and treatment period and was not significantly different from that of subcutaneous PMPA given at an equivalent dose. The favorable pharmacokinetic profile, marked antiviral efficacy, and low toxicity make bis(POC)-PMPA an attractive oral prodrug of PMPA that should be further pursued in clinical studies with patients infected with human immunodeficiency virus or hepatitis B virus.\n                  <\/jats:p>","DOI":"10.1128\/aac.42.7.1568","type":"journal-article","created":{"date-parts":[[2018,10,8]],"date-time":"2018-10-08T20:33:03Z","timestamp":1539030783000},"page":"1568-1573","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":129,"title":["Antiretroviral Efficacy and Pharmacokinetics of Oral Bis(isopropyloxycarbonyloxymethyl)9-(2-Phosphonylmethoxypropyl)adenine in Mice"],"prefix":"10.1128","volume":"42","author":[{"given":"Lieve","family":"Naesens","sequence":"first","affiliation":[{"name":"<!--label omitted: 1-->Rega Institute for Medical Research1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Norbert","family":"Bischofberger","sequence":"additional","affiliation":[{"name":"<!--label omitted: 2-->Gilead Sciences, Inc., Foster City, California 944042"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Augustijns","sequence":"additional","affiliation":[{"name":"<!--label omitted: 3-->Laboratory for Pharmacotechnology and Biopharmacy,3Katholieke Universiteit Leuven, B-3000 Leuven, Belgium, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pieter","family":"Annaert","sequence":"additional","affiliation":[{"name":"<!--label omitted: 3-->Laboratory for Pharmacotechnology and Biopharmacy,3Katholieke Universiteit Leuven, B-3000 Leuven, Belgium, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Van den Mooter","sequence":"additional","affiliation":[{"name":"<!--label omitted: 3-->Laboratory for Pharmacotechnology and Biopharmacy,3Katholieke Universiteit Leuven, B-3000 Leuven, Belgium, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murty N.","family":"Arimilli","sequence":"additional","affiliation":[{"name":"<!--label omitted: 2-->Gilead Sciences, Inc., Foster City, California 944042"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Choung U.","family":"Kim","sequence":"additional","affiliation":[{"name":"<!--label omitted: 2-->Gilead Sciences, Inc., Foster City, California 944042"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erik","family":"De Clercq","sequence":"additional","affiliation":[{"name":"<!--label omitted: 1-->Rega Institute for Medical Research1 and"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1023\/A:1012155717819","article-title":"Transport, uptake and metabolism of the bis(pivaloyloxymethyl)-ester prodrug of 9-(2-phosphonylmethoxyethyl)adenine in an in vitro cell culture system of the intestinal mucosa (Caco-2).","volume":"14","author":"Annaert P.","year":"1997","unstructured":"Annaert P. Kinget R. Naesens L. De Clercq E. Augustijns P. Transport, uptake and metabolism of the bis(pivaloyloxymethyl)-ester prodrug of 9-(2-phosphonylmethoxyethyl)adenine in an in vitro cell culture system of the intestinal mucosa (Caco-2). Pharm. Res. 14 1997 492 496","journal-title":"Pharm. Res."},{"key":"e_1_3_2_3_2","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1177\/095632029700800610","article-title":"Synthesis, in vitro biological evaluation, and oral bioavailability of 9-[2-phosphonylmethoxy)propyl]adenine (PMPA) prodrugs.","volume":"8","author":"Arimilli M. N.","year":"1997","unstructured":"Arimilli M. N. Kim C. U. Dougherty J. Mulato A. Oliyai R. Shaw J. P. Cundy K. C. Bischofberger N. Synthesis, in vitro biological evaluation, and oral bioavailability of 9-[2-phosphonylmethoxy)propyl]adenine (PMPA) prodrugs. Antivir. Chem. Chemother. 8 1997 557 564","journal-title":"Antivir. Chem. Chemother."},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.37.2.332"},{"key":"e_1_3_2_5_2","unstructured":"Barditch-Crovo\n              P.\n              Deeks\n              S.\n              Kahn\n              J.\n              Redpath\n              I.\n              Smith\n              A.\n              Hwang\n              F.\n              Hellmann\n              N.\n              Cundy\n              K.\n              Rooney\n              J.\n              Lietman\n              P.\n          PMPA: safety pharmacokinetics and antiretroviral activity when administered as a single dose and for seven consecutive days to patients with HIV infection. Presented at the 10th International Conference on Antiviral Research\n          1997"},{"key":"e_1_3_2_6_2","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1086\/514057","article-title":"Anti-human immunodeficiency virus (HIV) activity, safety, and pharmacokinetics of adefovir dipivoxyl (9-[2-(bis(pivaloyloxymethyl)phosphonylmethoxyethyl]adenine) in HIV-infected patients.","volume":"176","author":"Barditch-Crovo P.","year":"1997","unstructured":"Barditch-Crovo P. Toole J. Hendrix C. W. Cundy K. C. Ebeling D. Jaffe H. S. Lietman P. S. Anti-human immunodeficiency virus (HIV) activity, safety, and pharmacokinetics of adefovir dipivoxyl (9-[2-(bis(pivaloyloxymethyl)phosphonylmethoxyethyl]adenine) in HIV-infected patients. J. Infect. Dis. 176 1997 406 413","journal-title":"J. Infect. Dis."},{"key":"e_1_3_2_7_2","unstructured":"Bischofberger\n              N.\n              Naesens\n              L.\n              De Clercq\n              E.\n              Fridland\n              A.\n              Srinivas\n              R. V.\n              Robbins\n              B. L.\n              Arimilli\n              M.\n              Cundy\n              K. C.\n              Kim\n              C.\n              Lacy\n              S.\n              Lee\n              W.\n              Shaw\n              J.-P.\n              Oliyai\n              R.\n          Bis(POC)PMPA an orally bioavailable prodrug of the antiretroviral agent PMPA poster 214. Presented at the Fourth Conference on Retroviruses and Opportunistic Infections\n          1997"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.39.11.2401"},{"key":"e_1_3_2_9_2","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1023\/A:1018925723889","article-title":"Oral bioavailability of the antiretroviral agent 9-(2-phosphonylmethoxyethyl)adenine (PMEA) from three formulations of the prodrug bis(pivaloyloxymethyl)-PMEA in fasted male cynomolgus monkeys.","volume":"11","author":"Cundy K. C.","year":"1994","unstructured":"Cundy K. C. Fishback J. A. Shaw J.-P. Lee M. L. Soike K. F. Visor G. C. Lee W. A. Oral bioavailability of the antiretroviral agent 9-(2-phosphonylmethoxyethyl)adenine (PMEA) from three formulations of the prodrug bis(pivaloyloxymethyl)-PMEA in fasted male cynomolgus monkeys. Pharm. Res. 11 1994 839 843","journal-title":"Pharm. Res."},{"key":"e_1_3_2_10_2","unstructured":"Gilson\n              R. 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I-114.\n          Program and abstracts of the 37th Interscience Conference on Antimicrobial Agents and Chemotherapy.\n          1997\n          American Society for Microbiology\n          Washington D.C"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.40.1.22"},{"key":"e_1_3_2_14_2","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1093\/clinchem\/38.4.480","article-title":"Acyclic nucleoside phosphonates in plasma determined by high-performance liquid chromatography with fluorescence detection.","volume":"38","author":"Naesens L.","year":"1992","unstructured":"Naesens L. Balzarini J. De Clercq E. Acyclic nucleoside phosphonates in plasma determined by high-performance liquid chromatography with fluorescence detection. Clin. Chem. 38 1992 480 485","journal-title":"Clin. 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Agents Chemother. 40 1997 2586 2591","journal-title":"Antimicrob. Agents Chemother."}],"container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.42.7.1568","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.42.7.1568","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T11:03:37Z","timestamp":1645441417000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.42.7.1568"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1998,7]]},"references-count":20,"journal-issue":{"issue":"7","published-print":{"date-parts":[[1998,7]]}},"alternative-id":["10.1128\/AAC.42.7.1568"],"URL":"https:\/\/doi.org\/10.1128\/aac.42.7.1568","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[1998,7]]},"assertion":[{"value":"1997-10-03","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"1998-04-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"1998-07-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}