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Antimicrobial Agents and Chemotherapy, June 2007, p. 2130-2135, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01543-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Antiviral and Cellular Metabolism Interactions between Dexelvucitabine and Lamivudine{triangledown}

Brenda I. Hernandez-Santiago, Judy S. Mathew, Kim L. Rapp, Jason P. Grier, and Raymond F. Schinazi*

Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory School of Medicine/Veterans Affairs Medical Center, Decatur, Georgia 30033

Received 11 December 2006/ Returned for modification 11 January 2007/ Accepted 23 March 2007

Studies on cellular drug interactions with antiretroviral agents prior to clinical trials are critical to detect possible drug interactions. Herein, we demonstrated that two 2'-deoxycytidine antiretroviral agents, dexelvucitabine (known as ß-D-2',3'-didehydro-2',3'-dideoxy-5-fluorocytidine, DFC, D-d4FC, or RVT) and lamivudine (3TC), combined in primary human peripheral blood mononuclear (PBM) cells infected with human immunodeficiency virus 1 strain LAI (HIV-1LAI), resulted in additive-to-synergistic effects. The cellular metabolism of DFC and 3TC was studied in human T-cell lymphoma (CEM) and in primary human PBM cells to determine whether this combination caused any reduction in active nucleoside triphosphate (NTP) levels, which could decrease with their antiviral potency. Competition studies were conducted by coincubation of either radiolabeled DFC with different concentrations of 3TC or radiolabeled 3TC with different concentrations of DFC. Coincubation of radiolabeled 3TC with DFC at concentrations up to 33.3 µM did not cause any marked reduction in 3TC-triphosphate (TP) or any 3TC metabolites. However, a reduction in the level of DFC metabolites was noted at high concentrations of 3TC with radiolabeled DFC. DFC-TP levels in CEM and primary human PBM cells decreased by 88% and 94%, respectively, when high concentrations of 3TC (33.3 and 100 µM) were added, which may influence the effectiveness of DFC-5'-TP on the HIV-1 polymerase. The NTP levels remained well above the median (50%) inhibitory concentration for HIV-1 reverse transcriptase. These results suggest that both ß-D- and ß-L-2'-deoxycytidine analogs, DFC and 3TC, respectively, substrates of 2'-deoxycytidine kinase, could be used in a combined therapeutic modality. However, it may be necessary to decrease the dose of 3TC for this combination to prove effective.

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

{triangledown} Published ahead of print on 2 April 2007.

Antimicrobial Agents and Chemotherapy, June 2007, p. 2130-2135, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.01543-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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