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Antimicrobial Agents and Chemotherapy, August 2007, p. 2948-2953, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.01204-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

In Vitro Interactions between Apricitabine and Other Deoxycytidine Analogues{triangledown}

R. Bethell,* J. De Muys, J. Lippens, A. Richard, B. Hamelin, C. Ren, and P. Collins

ShireBioChem, Inc., Laval, Quebec, Canada

Received 25 September 2006/ Returned for modification 18 January 2007/ Accepted 13 May 2007

Apricitabine is a novel deoxycytidine analogue reverse transcriptase inhibitor that is under development for the treatment of human immunodeficiency virus type 1 (HIV-1) infection. Apricitabine is phosphorylated to its active triphosphate by deoxycytidine kinase, which is also responsible for the intracellular phosphorylation of lamivudine (3TC) and emtricitabine (FTC); hence, in vitro studies were performed to investigate possible interactions between apricitabine and these agents. Human peripheral blood mononuclear cells (PBMC) were incubated for 24 h with various concentrations of 3H-labeled or unlabeled apricitabine, 3TC, or FTC. Intracellular concentrations of parent compounds and their phosphorylated derivatives were measured by high-performance liquid chromatography. In other experiments, viral reverse transcriptase activity was measured in PBMC infected with HIV-1 bearing M184V in the presence of various concentrations of apricitabine and 3TC. [3H]apricitabine and [3H]3TC were metabolized intracellularly to form mono-, di-, and triphosphates. 3TC and FTC (1 to 10 µM) produced concentration-dependent decreases in apricitabine phosphorylation; in contrast, apricitabine at concentrations of up to 30 µM had no effect on the phosphorylation of 3TC or FTC. The combination of apricitabine and 3TC reduced the antiviral activity of apricitabine against HIV-1: apricitabine concentrations producing 50% inhibition of viral reverse transcriptase were increased two- to fivefold in the presence of 3TC. These findings suggest that nucleoside reverse transcriptase inhibitors with similar modes of action may show biochemical interactions that affect their antiviral efficacy. It is therefore essential that potential interactions between combinations of new and existing agents be thoroughly investigated before such combinations are introduced into clinical practice.

* Corresponding author. Mailing address: Boehringer-Ingelheim, Inc., 2100 Rue Cunard, Laval, Quebec H7S 2G5, Canada. Phone: (450) 682-4641. Fax: (450) 682-4642. E-mail: rbethell{at}lav.boehringer-ingelheim.com

{triangledown} Published ahead of print on 21 May 2007.

Antimicrobial Agents and Chemotherapy, August 2007, p. 2948-2953, Vol. 51, No. 8
0066-4804/07/$08.00+0     doi:10.1128/AAC.01204-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Gaffney, M. M, Belliveau, P. P, Spooner, L. M (2009). Apricitabine: A Nucleoside Reverse Transcriptase Inhibitor for HIV Infection. The Annals of Pharmacotherapy 43: 1676-1683 [Abstract] [Full Text]  


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