Pharmacokinetics of (-)-beta-_D-Dioxolane Guanine and Prodrug (-)-beta-_D-2,6-Diaminopurine Dioxolane in Rats and Monkeys

Abstract

(-)-beta-D-Dioxolane guanine (DXG) is a nucleoside analog possessing potent activity against human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2), and hepatitis B virus (HBV) in vitro. Owing to the limited aqueous solubility of DXG, (-)-beta-D-2,6-diaminopurine dioxolane (DAPD), a more water-soluble prodrug of DXG, is being developed for clinical use. The purpose of this study was to characterize the pharmacokinetics of DXG after administration of DXG and DAPD to rats and monkeys. After intravenous administration of DXG, plasma concentrations of the nucleoside declined in a biexponential manner, with a terminal-phase half-life of 0.44 +/- 0.14 hr (mean +/- SD) in rats and 2.3 hr in monkeys. Total clearance of DXG was 4.28 +/- 0.99 liters/hr/kg in rats and 0.72 liters/hr/kg in monkeys. Renal excretion of unchanged DXG accounted for approximately 50% of total clearance in both species. Steady state volume of distribution of DXG was 2.30 liters/kg in rats and 1.19 liters/kg in monkeys. After intravenous administration of DAPD to rats, prodrug concentrations declined with a half-life of 0.37 +/- 0.11 hr. DXG was rapidly generated from DAPD, with approximately 61% of the dose of DAPD being converted to DXG. After administration of DAPD to monkeys, only concentrations of metabolite DXG could be determined owing to rapid conversion of DAPD to DXG during sample collection. The half-lives of DAPD and DXG after intravenous administration determined from urinary excretion data were 0.8 +/- 0.4 and 1.6 +/- 0.2 hr, respectively. Oral bioavailability of DAPD was estimated to be approximately 30%.

Development of an Optimized Dose for Coformulation of Zidovudine with Drugs That Select for the K65R Mutation Using a Population Pharmacokinetic and Enzyme Kinetic Simulation Model

“…The in vitro selection of K65R, accompanied with moderate resistance, has been demonstrated for nonthymine NRTI, including abacavir sulfate (ABC), tenofovir disoproxil fumarate (TDF), zalcitabine, didanosine, adefovir dipivoxil and lamivudine (3TC), ␤-D-2Ј,3Ј-didehydro-2Ј,3Ј-dideoxy-5-fluorocytidine (D-d4FC, dexelvucitabine; Reverset), and ␤-D-(2R,4R)-1,3-dioxolane guanosine (DXG) (39,76,88,89). The guanosine nucleoside prodrug of DXG, amdoxovir [AMDX; (Ϫ)-␤-D-2,6-diaminopurine dioxolane (DAPD)] (12,25,31), is being developed by RFS Pharma, LLC, primarily for the second-line treatment of HIV-1 infections (35,52). The advantages of DXG include an increased sensitivity to M184V/I strains in vitro and activity against thymine analog mutations that may have been selected during previous antiretroviral therapy and 69SS double insert (36,37,55).…”

Novel Use of a Guanosine Prodrug Approach To Convert 2',3'-Didehydro-2',3'-Dideoxyguanosine into a Viable Antiviral Agent

“…Abacavir and DAPD are metabolized to guanosine analogs by deamination and phosphorylated to make the active triphosphates (6,7). The presence of the amino group improved the lipophilicity, solubility, and oral bioavailability of these guanosine analogs (1,5). The presence of the cyclopropylsubstituted secondary amine of abacavir also improved its absorption into the central nervous system (5).…”

Molecular Pharmacology of Nucleoside and Nucleotide HIV-1 Reverse Transcriptase Inhibitors

“…However, it demonstrates poor solubility and limited oral bioavailability in monkeys (Chen et al, 1996). The analog 1-β-D-2,6-diaminopurine dioxolane (amdoxovir; Figure 8) also exhibits antiviral activity and is more water soluble and orally bioavailable (Chen et al, 1999;Kim et al, 1993)). Amdoxovir serves as a prodrug for DXG by deamination at the 6-position by adenosine deaminase (Gu et al, 1999).…”

“…8. Metabolic pathway of amdoxovir woodchucks, and rats with approximately 61 % of the dose converted to DXG (Chen et al, 1996;Chen et al, 1999;Rajagopalan et al, 1996). The oral bioavailability of amdoxovir is estimated to be 30% (Chen et al, 1999).…”

“…Metabolic pathway of amdoxovir woodchucks, and rats with approximately 61 % of the dose converted to DXG (Chen et al, 1996;Chen et al, 1999;Rajagopalan et al, 1996). The oral bioavailability of amdoxovir is estimated to be 30% (Chen et al, 1999). Following oral administration of amdoxovir to HIVinfected patients, peak plasma levels of amdoxivir and DXG were reached within 2 hours (Thompson et al, 2005).…”