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.

Abstract:

:(-)-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.

authors

Chen H,Boudinot FD,Chu CK,Mcclure HM,Schinazi RF

doi

10.1128/AAC.40.10.2332

subject

Has Abstract

pub_date

1996-10-01 00:00:00

pages

2332-6

issue

10

eissn

0066-4804

issn

1098-6596

journal_volume

40

pub_type

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