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Pharmacokinetics of the antiviral agent beta-D-2'-deoxy-2'-fluoro-2'-C-methylcytidine in rhesus monkeys. 2007

Ghazia Asif, and Selwyn J Hurwitz, and Junxing Shi, and Brenda I Hernandez-Santiago, and Raymond F Schinazi
Veterans Affairs Medical Center, Medical Research 151H, Decatur, GA 30033, USA.

beta-D-2'-Deoxy-2'-fluoro-2'-C-methylcytidine (PSI-6130) is an effective inhibitor of hepatitis C virus (HCV) replication in vitro. The purpose of this study was to evaluate the single-dose pharmacokinetics of PSIota-6130 in rhesus monkeys following intravenous (i.v.) and oral administration. Noncompartmental analysis of the serum data obtained following oral and i.v. administration was performed. Pharmacokinetic studies with rhesus monkeys indicated slow and incomplete absorption with a mean absorption time (MAT) of 4.6 h and an oral bioavailability of 24.0% +/- 14.3% (mean +/- standard deviation), with comparable mean apparent half-lives following i.v. (4.54 +/- 3.98 h) and oral (5.64 +/- 1.13 h) administrations. The average percentages of the total dose recovered unchanged and in deaminated form in the urine were 32.9% +/- 12.6% and 18.9% +/- 6.6% (i.v.) and 6.0% +/- 3.9% and 3.9% +/- 1.0% (oral), respectively. The total bioavailability, taking into account the parent drug and its deaminated metabolite 2'-deoxy-2'-fluoro-2'-C-methyluridine (PSI-6206), was 64% +/- 26%. PSI-6130 was present in the cerebrospinal fluid after oral and i.v. dosing. However, no deamination of radiolabeled PSI-6130 was detected after 8 h of incubation in monkey and human whole blood. An N(4)-modified prodrug of PSI-6130 (PSI-6419) was orally administered to monkeys, but it failed to improve the oral bioavailability of PSI-6130. Further studies are warranted to improve the oral bioavailability and reduce the deamination of PSI-6130 in order to explore the potential of this drug for the treatment of HCV-infected individuals.

UI MeSH Term Description Entries
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
D011355 Prodrugs A compound that, on administration, must undergo chemical conversion by metabolic processes before becoming the pharmacologically active drug for which it is a prodrug. Drug Precursor,Drug Precursors,Pro-Drug,Prodrug,Pro-Drugs,Precursor, Drug,Precursors, Drug,Pro Drug,Pro Drugs
D002555 Cerebrospinal Fluid A watery fluid that is continuously produced in the CHOROID PLEXUS and circulates around the surface of the BRAIN; SPINAL CORD; and in the CEREBRAL VENTRICLES. Cerebro Spinal Fluid,Cerebro Spinal Fluids,Cerebrospinal Fluids,Fluid, Cerebro Spinal,Fluid, Cerebrospinal,Fluids, Cerebro Spinal,Fluids, Cerebrospinal,Spinal Fluid, Cerebro,Spinal Fluids, Cerebro
D003841 Deoxycytidine A nucleoside component of DNA composed of CYTOSINE and DEOXYRIBOSE. Cytosine Deoxyribonucleoside,Cytosine Deoxyriboside,Deoxyribonucleoside, Cytosine,Deoxyriboside, Cytosine
D004791 Enzyme Inhibitors Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. Enzyme Inhibitor,Inhibitor, Enzyme,Inhibitors, Enzyme
D005260 Female Females
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000284 Administration, Oral The giving of drugs, chemicals, or other substances by mouth. Drug Administration, Oral,Administration, Oral Drug,Oral Administration,Oral Drug Administration,Administrations, Oral,Administrations, Oral Drug,Drug Administrations, Oral,Oral Administrations,Oral Drug Administrations
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

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