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.
Full Text
The Full Text of this article is available as a PDF (192.7 KB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Burger D. M., Kraaijeveld C. L., Meenhorst P. L., Mulder J. W., Koks C. H., Bult A., Beijnen J. H. Penetration of zidovudine into the cerebrospinal fluid of patients infected with HIV. AIDS. 1993 Dec;7(12):1581–1587. doi: 10.1097/00002030-199312000-00006. [DOI] [PubMed] [Google Scholar]
- Collins J. M., Klecker R. W., Jr, Kelley J. A., Roth J. S., McCully C. L., Balis F. M., Poplack D. G. Pyrimidine dideoxyribonucleosides: selectivity of penetration into cerebrospinal fluid. J Pharmacol Exp Ther. 1988 May;245(2):466–470. [PubMed] [Google Scholar]
- Ho D. D., Rota T. R., Schooley R. T., Kaplan J. C., Allan J. D., Groopman J. E., Resnick L., Felsenstein D., Andrews C. A., Hirsch M. S. Isolation of HTLV-III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immunodeficiency syndrome. N Engl J Med. 1985 Dec 12;313(24):1493–1497. doi: 10.1056/NEJM198512123132401. [DOI] [PubMed] [Google Scholar]
- Kim H. O., Schinazi R. F., Nampalli S., Shanmuganathan K., Cannon D. L., Alves A. J., Jeong L. S., Beach J. W., Chu C. K. 1,3-dioxolanylpurine nucleosides (2R,4R) and (2R,4S) with selective anti-HIV-1 activity in human lymphocytes. J Med Chem. 1993 Jan 8;36(1):30–37. doi: 10.1021/jm00053a004. [DOI] [PubMed] [Google Scholar]
- Rocci M. L., Jr, Jusko W. J. LAGRAN program for area and moments in pharmacokinetic analysis. Comput Programs Biomed. 1983 Jun;16(3):203–216. doi: 10.1016/0010-468x(83)90082-x. [DOI] [PubMed] [Google Scholar]