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.
Rossi
Luigia
L
Institute of Biochemistry G. Fornaini and Institute of Hygiene, University of Urbino, 61029 Urbino, Italy.
Dominici
Sabrina
S
Serafini
Sonja
S
Casabianca
Anna
A
Cerasi
Aurora
A
Chiarantini
Laura
L
Celeste
Angela Gabriela
AG
Cappellacci
Loredana
L
Franchetti
Palmarisa
P
Grifantini
Mario
M
Magnani
Mauro
M
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