Pharmacokinetics of (-)-β-D-2,6-Diaminopurine Dioxolane and its Metabolite, Dioxolane Guanosine, in Woodchucks (Marmota Monax)

Abstract

SummaryThe woodchuck (Marmota monax) is a useful animal model for evaluating the in-vivo efficacy of antiviral agents against hepatitis B viral infection (HBV). The pharmacokinetics of a newly synthesized antiviral agent (-H-o-2,6-diaminopurine dioxolane (DAPD) in woodchucks is reported. DAPD is a nucleoside analogue, having potent and selective activity against human immunodeficiency virus and HBV in vitro. DAPD is susceptible to deamination in vivo by the ubiquitously present enzyme adenosine deaminase yielding the active metabolite dioxolane guanosine (DXG). The pharmacokinetics of DAPD and DXG were characterized following intravenous (Lv.) and oral (p.o.) administration of 20 mg kg-1 of DAPD to woodchucks. Plasma and urine samples were collected, and nucleoside concentrations were determined by HPLC. Following intravenous administration, the halflife of DAPD averaged 6.7 ± 4.3 h, and that of DXG averaged 17.6 ± 14.5 h. The mean total clearance and steady state volume of distribution of DAPD were 0.33 ± 0.14 L h kg-1 and 1.76 ± 0.65 L kg-\ respectively. The oral bioavailability of DAPD ranged from 3.7-8.2%; however, the apparent availability of DXG following oral administration of DAPD was 10.5-53%.

Tissue biodistribution and blood clearance rates of intravenously administered carbon nanotube radiotracers

“…Polyplexes formed Conversely, the blood circulation half-life of the f-CNT in this study is significantly shorter than that of other functionalized C 60 fullerenes, which have been shown to have a blood half-life of 6.8 h after i.v. administration (43). These fullerenes do not appear to be excreted through the urine and seem to have a high level of affinity for plasma proteins.…”

[60]Fullerene Amino Acids and Related Derivatives

“…[60]Fullerene derivatives exhibit a range of interesting biological activities including inhibition of HIV enzymes [4][5][6][7][8][9][10][11][12] , photoinduced cytotoxicity via selective cleavage of DNA [13][14][15][16][17] and as a smooth muscle relaxant [18][19][20] . In addition, other interesting reports of fullerene derivatives of biologically significant molecules such as lipids 21 , saccharides 22 , oligonucleotides [23][24] and amino acids have appeared in the literature.…”

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

“…In vitro, amdoxovir bound adenosine deaminase as efficiently as adenosine, however amdoxovir was deaminated 540-fold slower than adenosine (Furman et al, 2001). Only DXG-triphosphate was detected in PBMC and CEM cells following exposure to DXG or amdoxovir (Rajagopalan et al, 1994;Rajagopalan et al, 1996). DXG is phosphorylated to DXG-MP by 5'-nucleotidase using IMP as a phosphate donor (Feng et al, 2004).…”

“…Amdoxovir was eliminated from plasma with half-life of 1 -2 hours by conversion to DXG, whereas DXG demonstrated a longer half-life of 4 -7 hours. In animal studies amdoxovir toxicities included obstructive nephropathy, uremia, islet cell atrophy, hyperglycemia, and lens opacities (Rajagopalan et al, 1996). In a phase I/II clinical study 4 of 18 patients developed nongradeable lens opacities (Thompson et al, 2005).…”

“…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).…”