{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T07:38:03Z","timestamp":1791013083849,"version":"4.1.0"},"reference-count":0,"publisher":"American Society for Microbiology","issue":"1","license":[{"start":{"date-parts":[[1996,1,1]],"date-time":"1996-01-01T00:00:00Z","timestamp":820454400000},"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":[[1996,1]]},"abstract":"<jats:p>Lipophilic ester prodrugs of 9-(2-phosphonylmethoxyethyl)adenine (PMEA), i.e., bis(pivaloyloxymethyl)-PMEA [bis(POM)-PMEA] and diphenyl-PMEA, have been synthesized in an attempt to increase the oral bioavailability of this broad-spectrum antiviral agent. The antiretroviral efficacy was determined in severe combined immune deficiency (SCID) mice infected with Moloney murine sarcoma virus (MSV). They were treated twice daily for 5 days after infection. Oral treatment with bis(POM)-PMEA at a dose equivalent to 100 or 50 mg of PMEA per kg of body weight per day proved markedly effective in delaying MSV-induced tumor formation and death of the mice. Oral bis(POM)-PMEA afforded anti-MSV efficacy equal to that of subcutaneous PMEA given at equimolar doses. Oral treatment with PMEA or diphenyl-PMEA proved less efficient. Similarly, in mice infected with Friend leukemia virus (FLV), oral treatment with bis(POM)-PMEA at a dose equivalent to 100 or 50 mg of PMEA per kg per day effected a marked inhibition of FLV-induced splenomegaly (87 and 48% inhibition, respectively), the efficacy being equal to that of PMEA given subcutaneously at equivalent doses. Pharmacokinetic experiments with mice showed that the oral bioavailabilities of PMEA following oral gavage of bis(POM)-PMEA, diphenyl-PMEA, or PMEA (at a dose equivalent to 50 mg of PMEA per kg) were 53,3, and 16%, respectively. These data were calculated from the levels of free PMEA in plasma. Also, the recoveries of free PMEA in the urine upon oral administration of bis(POM)-PMEA, diphenyl-PMEA, or PMEA (at a dose equivalent to 25 mg of PMEA per kg) were 48, 4, and 7%, respectively. Oral bis(POM)-PMEA was not recovered from plasma, suggesting that it was readily cleaved to free PMEA. In contrast, diphenyl-PMEA was not efficiently cleaved to free PMEA, resulting in a rather low oral bioavailability of PMEA from this prodrug. Bis(POM)-PMEA appears to be an efficient oral prodrug of PMEA that deserves further clinical evaluation in human immunodeficiency virus-infected individuals.<\/jats:p>","DOI":"10.1128\/aac.40.1.22","type":"journal-article","created":{"date-parts":[[2018,10,9]],"date-time":"2018-10-09T00:24:34Z","timestamp":1539044674000},"page":"22-28","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":77,"title":["Antiretroviral activity and pharmacokinetics in mice of oral bis(pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine, the bis(pivaloyloxymethyl) ester prodrug of 9-(2-phosphonylmethoxyethyl)adenine"],"prefix":"10.1128","volume":"40","author":[{"given":"L","family":"Naesens","sequence":"first","affiliation":[{"name":"Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. lieve.naesens\/rega.kuleuven.ac.be"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J","family":"Balzarini","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. lieve.naesens\/rega.kuleuven.ac.be"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N","family":"Bischofberger","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. lieve.naesens\/rega.kuleuven.ac.be"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E","family":"De Clercq","sequence":"additional","affiliation":[{"name":"Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. lieve.naesens\/rega.kuleuven.ac.be"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","container-title":["Antimicrobial Agents and Chemotherapy"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.40.1.22","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.asm.org\/doi\/pdf\/10.1128\/AAC.40.1.22","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,21]],"date-time":"2022-02-21T20:00:27Z","timestamp":1645473627000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.asm.org\/doi\/10.1128\/AAC.40.1.22"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1996,1]]},"references-count":0,"journal-issue":{"issue":"1","published-print":{"date-parts":[[1996,1]]}},"alternative-id":["10.1128\/AAC.40.1.22"],"URL":"https:\/\/doi.org\/10.1128\/aac.40.1.22","relation":{},"ISSN":["0066-4804","1098-6596"],"issn-type":[{"value":"0066-4804","type":"print"},{"value":"1098-6596","type":"electronic"}],"subject":[],"published":{"date-parts":[[1996,1]]},"assertion":[{"value":"1996-01-01","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}