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Antimicrobial Agents and Chemotherapy, September 2007, p. 3177-3184, Vol. 51, No. 9
0066-4804/07/$08.00+0     doi:10.1128/AAC.00325-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Antiviral Effect of Orally Administered (–)-ß-D-2-Aminopurine Dioxolane in Woodchucks with Chronic Woodchuck Hepatitis Virus Infection

Gastrointestinal Unit, Department of Clinical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, New York 14853,¹ Department of Pediatrics, Laboratory of Biochemical Pharmacology, Emory University School of Medicine, and Veterans Affairs Medical Center, Decatur, Georgia 30033,² College of Pharmacy, The University of Georgia, Athens, Georgia 30602,³ Department of Microbiology and Immunology, Georgetown University Medical Center, Washington, DC 20057⁴

Received 8 March 2007/ Returned for modification 4 April 2007/ Accepted 26 June 2007

(–)-ß-D-2-Aminopurine dioxolane (APD) is a nucleoside prodrug that is efficiently converted to 9-(ß-D-1,3-dioxolan-4-yl)guanine (DXG). DXG has antiviral activity in vitro against hepatitis B virus (HBV) but limited aqueous solubility, making it difficult to administer orally to HBV-infected individuals. APD is more water soluble than DXG and represents a promising prodrug for the delivery of DXG. A placebo-controlled, dose-ranging efficacy and pharmacokinetic study was conducted with woodchucks that were chronically infected with woodchuck hepatitis virus (WHV). APD was efficiently converted to DXG after oral and intravenous administrations of APD, with serum concentrations of DXG being higher following oral administration than following intravenous administration, suggestive of a considerable first-pass intestinal and/or hepatic metabolism. APD administered orally at 1, 3, 10, and 30 mg/kg of body weight per day for 4 weeks produced a dose-dependent antiviral response. Doses of 3 and 10 mg/kg/day reduced serum WHV viremia by 0.4 and 0.7 log₁₀ copies/ml, respectively. The 30-mg/kg/day dose resulted in a more pronounced, statistically significant decline in serum WHV viremia of 1.9 log₁₀ copies/ml and was associated with a 1.5-fold reduction in hepatic WHV DNA. Individual woodchucks within the highest APD dose group that had declines in serum WHV surface antigen levels, WHV viremia, and hepatic WHV DNA also had reductions in hepatic WHV RNA. There was a prompt recrudescence of WHV viremia following drug withdrawal. Therefore, oral administration of APD for 4 weeks was safe in the woodchuck model of chronic HBV infection, and the effect on serum WHV viremia was dose dependent.

Published ahead of print on 2 July 2007.