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.
abstract: 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.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium. lieve.naesens/rega.kuleuven.ac.be
authors.forename: L
authors.initials: L
authors.lastname: Naesens
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: N
authors.initials: N
authors.lastname: Bischofberger
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D000998:Antiviral Agents / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D005622:Friend murine leukemia virus / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000821:virology; D051379:Mice; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D008980:Moloney murine sarcoma virus / Q000187:drug effects; D063065:Organophosphonates; D011355:Prodrugs / Q000493:pharmacokinetics* / Q000494:pharmacology*; D051381:Rats; D012190:Retroviridae / Q000187:drug effects*; D012192:Retroviridae Infections / Q000188:drug therapy / Q000821:virology; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000517:prevention & control; D014412:Tumor Virus Infections / Q000188:drug therapy
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D063065:Organophosphonates; D011355:Prodrugs; C089823:bis(pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine; C103014:diphenyl-9-(2-phosphonylmethoxyethyl)adenine; C053001:adefovir; D000225:Adenine