Pharmacokinetics of (-)-beta-D-2-aminopurine dioxolane and (-)-beta-D-2-amino-6-chloropurine dioxolane and their antiviral metabolite (-)-beta-D-dioxolane guanine in rhesus monkeys.
(-)-beta-D-2-Aminopurine dioxolane (APD) and (-)-beta-D-2-amino-6-chloropurine dioxolane (ACPD) are recently synthesized dioxolanylpurine nucleoside derivatives being developed as potential prodrugs for the antiviral nucleoside analog (-)-beta-D-dioxolane guanine (DXG). In vitro, APD and ACPD are converted to DXG by xanthine oxidase and adenosine deaminase, respectively. The purpose of this study was to evaluate the preclinical pharmacokinetics of APD and ACPD and their potential for generating sustained levels of the parent nucleoside, DXG, in rhesus monkeys following oral administration. Both nucleoside derivatives were rapidly absorbed, with similar peak concentrations achieved within 1 h after administration. However, concentrations of APD were more markedly sustained than those of ACPD. Both prodrugs yielded DXG, but significantly higher serum concentrations of DXG and area under the concentration-time curve values were observed following administration of APD. In addition, APD produced higher concentrations of prodrug and DXG in cerebrospinal fluid than did ACPD. Thus, the results of this pharmacokinetic study suggest that APD is likely to serve as a better prodrug of DXG and should be considered for clinical trials for antiviral therapy against human immunodeficiency virus and hepatitis B virus.
Department of Pharmaceutics, College of Pharmacy, University of Georgia, Athens 30602, USA.
H
H
Chen
F D
FD
Boudinot
C K
CK
Chu
H M
HM
Mcclure
R F
RF
Schinazi
D000818:Animals; D000998:Antiviral Agents / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics*; D001772:Blood Cell Count; D004148:Dioxolanes / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006151:Guanosine / Q000031:analogs & derivatives* / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D011687:Purines / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics* / Q000494:pharmacology*
D000998:Antiviral Agents; D004148:Dioxolanes; D011687:Purines; C098394:dioxolane guanosine; D006151:Guanosine; C104068:4-(2-amino-6-chloro-9H-purin-9-yl)-1,3-dioxolane-2-methanol; C104069:(4-2-aminopurin-9-yl)-1,3-dioxolane-2-methanol