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Antimicrobial Agents and Chemotherapy, December 2004, p. 4636-4642, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4636-4642.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Metabolism of the Anti-Hepatitis C Virus Nucleoside ß-D-N4-Hydroxycytidine in Different Liver Cells

Brenda I. Hernandez-Santiago,1 Thierry Beltran,1 Lieven Stuyver,2 Chung K. Chu,3 and Raymond F. Schinazi1*

Department of Pediatrics, Emory School of Medicine, and Veterans Affairs Medical Center, Decatur,1 Pharmasset Inc., Tucker,2 College of Pharmacy, University of Georgia, Athens, Georgia3

Received 20 April 2004/ Returned for modification 26 June 2004/ Accepted 17 August 2004

ß-D-N4-Hydroxycytidine (NHC) was found to have selective anti-hepatitis C virus (HCV) activity in the HCV replicon system (clone A). The intracellular metabolism of tritiated NHC was investigated in the HCV replicon system, Huh-7 cells, HepG2 cells, and primary human hepatocytes. Incubation of cells with 10 µM radiolabeled NHC demonstrated extensive and rapid phosphorylation in all liver cells. Besides the 5'-mono, -di-, and -triphosphate metabolites of NHC, other metabolites were characterized. These included cytidine and uridine mono-, di-, and triphosphates. UTP was the predominant early metabolite in Huh-7 cells and primary human hepatocytes, suggesting deamination of NHC as the primary catabolic pathway. The intracellular half-lives of radiolabeled NHC-triphosphate and of CTP and UTP derived from NHC incubation in Huh-7 cells were calculated to be 3.0 ± 1.3, 10.4 ± 3.3, and 13.2 ± 3.5 h (means ± standard deviations), respectively. Studies using monkey and human whole blood demonstrated more-rapid deamination and oxidation in monkey cells than in human cells, suggesting that NHC may not persist long enough in plasma to be delivered to liver cells.

* Corresponding author. Mailing address: Veterans Affairs Medical Center, Medical Research 151H, 1670 Clairmont Rd., Decatur, GA 30033. Phone: (404) 728-7711. Fax: (404) 728-7726. E-mail: rschina{at}emory.edu.

Antimicrobial Agents and Chemotherapy, December 2004, p. 4636-4642, Vol. 48, No. 12
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.12.4636-4642.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Matthes, E., Funk, A., Krahn, I., Gaertner, K., von Janta-Lipinski, M., Lin, L., Will, H., Sirma, H. (2007). Strong and Selective Inhibitors of Hepatitis B Virus Replication among Novel N4-Hydroxy- and 5-Methyl-{beta}-L-Deoxycytidine Analogues. Antimicrob. Agents Chemother. 51: 2523-2530 [Abstract] [Full Text]  


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