Pharmacokinetic and antiretroviral activity in mice of oral [P(1),P(2)-bis[2-(adenin-9-yl)ethoxymethyl]phosphonate], a prodrug of 9-(2-phosphonylmethoxyethyl)adenine.
9-(2-Phosphonylmethoxyethyl)adenine (PMEA) is an antiviral drug with activity against herpes viruses, Epstein-Barr virus and retroviruses, including the human immunodeficiency virus. Unfortunately, oral PMEA administration, as required for long-term therapy, is hindered by its low bioavailability. In the present study, the synthesis, oral bioavailability and antiretroviral activity of a new prodrug of PMEA, consisting of two molecules of PMEA bound together by a P-O-P bond (Bis-PMEA), are reported. Pharmacokinetic experiments in mice showed that the oral bioavailabilities of PMEA following oral gavage of Bis-PMEA or PMEA (at a dose equivalent to 28 mg of PMEA/kg) were 50.8 and 13.5%, respectively. These results correlate with the antiviral efficacy of Bis-PMEA administered orally at a dose equivalent to 50 mg/kg of PMEA in C57 BL/6 mice infected with the retroviral complex LP-BM5. Oral treatment with Bis-PMEA proved to be more effective than oral treatment with PMEA given at equimolar doses. Moreover, oral Bis-PMEA was more effective than intraperitoneal PMEA (50 mg/kg) in reducing lymphoadenopathy, hypergammaglobulinaemia and lymph node proviral DNA content, overall in the first weeks post virus inoculation. Bis-PMEA thus appears to be an efficient oral prodrug of PMEA without significant toxicity, at least in this mouse model.
Institute of Biochemistry G. Fornaini and Institute of Hygiene, University of Urbino, 61029 Urbino, Italy.
Luigia
L
Rossi
Sabrina
S
Dominici
Sonja
S
Serafini
Anna
A
Casabianca
Aurora
A
Cerasi
Laura
L
Chiarantini
Angela Gabriela
AG
Celeste
Loredana
L
Cappellacci
Palmarisa
P
Franchetti
Mario
M
Grifantini
Mauro
M
Magnani
D000225:Adenine / Q000031:analogs & derivatives / Q000097:blood* / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use; D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000097:blood* / Q000138:chemical synthesis / Q000627:therapeutic use; D001682:Biological Availability; D001772:Blood Cell Count; D002851:Chromatography, High Pressure Liquid; D004279:DNA, Viral / Q000032:analysis; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D008198:Lymph Nodes / Q000821:virology; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D063065:Organophosphonates; D016133:Polymerase Chain Reaction; D011355:Prodrugs; D012190:Retroviridae / Q000187:drug effects*; D012192:Retroviridae Infections / Q000097:blood / Q000188:drug therapy* / Q000821:virology; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D004279:DNA, Viral; D063065:Organophosphonates; D011355:Prodrugs; C430424:bis-9-(2-phosphonylmethoxyethyl)adenine; C053001:adefovir; D000225:Adenine