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Antimicrobial Agents and Chemotherapy, July 1998, p. 1799-1804, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Metabolism of 2',3'-Dideoxy-2',3'-Didehydro-beta -L(-)-5-Fluorocytidine and Its Activity in Combination with Clinically Approved Anti-Human Immunodeficiency Virus beta -D(+) Nucleoside Analogs In Vitro

Ginger E. Dutschman, Edward G. Bridges, Shwu-Huey Liu, Elizabeth Gullen, Xin Guo, Marina Kukhanova, and Yung-Chi Cheng*

Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut 06520

Received 14 November 1997/Returned for modification 21 February 1998/Accepted 10 April 1998

2',3'-Dideoxy-2',3'-didehydro-beta -L(-)-5-fluorocytidine [L(-)Fd4C] has been reported to be a potent inhibitor of the human immunodeficiency virus (HIV) in cell culture. In the present study the antiviral activity of this compound in two-drug combinations and its intracellular metabolism are addressed. The two-drug combination of L(-)Fd4C plus 2',3'-didehydro-2',3'-dideoxythymidine (D4T, or stavudine) or 3'-azido-3'-deoxythymidine (AZT, or zidovudine) synergistically inhibited replication of HIV in vitro. Additive antiviral activity was observed with L(-)Fd4C in combination with 2',3'-dideoxycytidine (ddC, or zalcitabine) or 2',3'-dideoxyinosine (ddI, or didanosine). This beta -L(-) nucleoside analog has no activity against mitochondrial DNA synthesis at concentrations up to 10 µM. As we previously reported for other beta -L(-) nucleoside analogs, L(-)Fd4C could protect against mitochondrial toxicity associated with D4T, ddC, and ddI. Metabolism studies showed that this drug is converted intracellularly to its mono-, di-, and triphosphate metabolites. The enzyme responsible for monophosphate formation was identified as cytoplasmic deoxycytidine kinase, and the Km is 100 µM. L(-)Fd4C was not recognized in vitro by human mitochondrial deoxypyrimidine nucleoside kinase. Also, L(-)Fd4C was not a substrate for deoxycytidine deaminase. L(-)Fd4C 5'-triphosphate served as an alternative substrate to dCTP for incorporation into DNA by HIV reverse transcriptase. The favorable anti-HIV activity and protection from mitochondrial toxicity by L(-)Fd4C in two-drug combinations favors the further development of L(-)Fd4C as an anti-HIV agent.

* Corresponding author. Mailing address: Department of Pharmacology, Yale University School of Medicine, 333 Cedar St., P.O. Box 802066, New Haven, CT 06520-8066. Phone: (203) 785-7118. Fax: (203) 785-7129. E-mail: cheng.lab{at}yale.edu.

Antimicrobial Agents and Chemotherapy, July 1998, p. 1799-1804, Vol. 42, No. 7
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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