Biomaterial Database

Pharmacology and pharmacokinetics of the antiviral agent beta-D-2',3'-dideoxy-3'-oxa-5-fluorocytidine in cells and rhesus monkeys. 2005

Brenda I Hernandez-Santiago, and Huachun Chen, and Ghazia Asif, and Thierry Beltran, and Shuli Mao, and Selwyn J Hurwitz, and Jason Grier, and Harold M McClure, and Chung K Chu, and Dennis C Liotta, and Raymond F Schinazi

Department of Pediatrics, Emory School of Medicine/Veterans Affairs Medical Center, Medical Research 151H, 1670 Clairmont Rd., Decatur, Georgia 30033, SUA.

Beta-D-2',3'-dideoxy-3'-oxa-5-fluorocytidine (D-FDOC) is an effective inhibitor of human immunodeficiency virus 1 (HIV-1) and HIV-2, simian immunodeficiency virus, and hepatitis B virus (HBV) in vitro. The purpose of this study was to evaluate the intracellular metabolism of d-FDOC in human hepatoma (HepG2), human T-cell lymphoma (CEM), and primary human peripheral blood mononuclear (PBM) cells by using tritiated compound. By 24 h, the levels of D-FDOC-triphosphate (D-FDOC-TP) were 2.8 +/- 0.4, 6.7 +/- 2.3, and 2.0 +/- 0.1 pmol/10(6) cells in HepG2, CEM, and primary human PBM cells, respectively. Intracellular D-FDOC-TP concentrations remained greater than the 50% inhibitory concentration for HIV-1 reverse transcriptase for up to 24 h after removal of the drug from cell cultures. In addition to d-FDOC-monophosphate (D-FDOC-MP), -diphosphate (D-FDOC-DP), and -TP, D-FDOC-DP-ethanolamine and d-FDOC-DP-choline were detected in all cell extracts as major intracellular metabolites. D-FDOC was not a substrate for Escherichia coli thymidine phosphorylase. No toxicity was observed in mice given D-FDOC intraperitoneally for 6 days up to a dose of 100 mg/kg per day. Pharmacokinetic studies in rhesus monkeys indicated that D-FDOC has a t(1/2) of 2.1 h in plasma and an oral bioavailability of 38%. The nucleoside was excreted unchanged primary in the urine, and no metabolites were detected in plasma or urine. These results suggest that further safety and pharmacological studies are warranted to assess the potential of this nucleoside for the treatment of HIV- and HBV-infected individuals.

UI	MeSH Term	Description	Entries
D007963	Leukocytes, Mononuclear	Mature LYMPHOCYTES and MONOCYTES transported by the blood to the body's extravascular space. They are morphologically distinguishable from mature granulocytic leukocytes by their large, non-lobed nuclei and lack of coarse, heavily stained cytoplasmic granules.	Mononuclear Leukocyte,Mononuclear Leukocytes,PBMC Peripheral Blood Mononuclear Cells,Peripheral Blood Human Mononuclear Cells,Peripheral Blood Mononuclear Cell,Peripheral Blood Mononuclear Cells,Leukocyte, Mononuclear
D008253	Macaca mulatta	A species of the genus MACACA inhabiting India, China, and other parts of Asia. The species is used extensively in biomedical research and adapts very well to living with humans.	Chinese Rhesus Macaques,Macaca mulatta lasiota,Monkey, Rhesus,Rhesus Monkey,Rhesus Macaque,Chinese Rhesus Macaque,Macaca mulatta lasiotas,Macaque, Rhesus,Rhesus Macaque, Chinese,Rhesus Macaques,Rhesus Macaques, Chinese,Rhesus Monkeys
D008297	Male		Males
D003562	Cytidine	A pyrimidine nucleoside that is composed of the base CYTOSINE linked to the five-carbon sugar D-RIBOSE.	Cytosine Ribonucleoside,Cytosine Riboside,Ribonucleoside, Cytosine,Riboside, Cytosine
D004926	Escherichia coli	A species of gram-negative, facultatively anaerobic, rod-shaped bacteria (GRAM-NEGATIVE FACULTATIVELY ANAEROBIC RODS) commonly found in the lower part of the intestine of warm-blooded animals. It is usually nonpathogenic, but some strains are known to produce DIARRHEA and pyogenic infections. Pathogenic strains (virotypes) are classified by their specific pathogenic mechanisms such as toxins (ENTEROTOXIGENIC ESCHERICHIA COLI), etc.	Alkalescens-Dispar Group,Bacillus coli,Bacterium coli,Bacterium coli commune,Diffusely Adherent Escherichia coli,E coli,EAggEC,Enteroaggregative Escherichia coli,Enterococcus coli,Diffusely Adherent E. coli,Enteroaggregative E. coli,Enteroinvasive E. coli,Enteroinvasive Escherichia coli
D005260	Female		Females
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000818	Animals	Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA.	Animal,Metazoa,Animalia
D000998	Antiviral Agents	Agents used in the prophylaxis or therapy of VIRUS DISEASES. Some of the ways they may act include preventing viral replication by inhibiting viral DNA polymerase; binding to specific cell-surface receptors and inhibiting viral penetration or uncoating; inhibiting viral protein synthesis; or blocking late stages of virus assembly.	Antiviral,Antiviral Agent,Antiviral Drug,Antivirals,Antiviral Drugs,Agent, Antiviral,Agents, Antiviral,Drug, Antiviral,Drugs, Antiviral
D013939	Thymidine Phosphorylase	An enzyme that catalyzes the transfer of 2-deoxy-D-ribose from THYMIDINE to orthophosphate, thereby liberating thymidine.	PD-ECGF,Platelet-Derived Endothelial Cell Growth Factor,Gliostatin,Platelet Derived Endothelial Cell Growth Factor