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Antimicrobial Agents and Chemotherapy, February 2008, p. 598-605, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.01122-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Entecavir for Treatment of Hepatitis B Virus Displays No In Vitro Mitochondrial Toxicity or DNA Polymerase Gamma Inhibition{triangledown}

Charles E. Mazzucco, Robert K. Hamatake,{dagger} Richard J. Colonno, and Daniel J. Tenney*

Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut

Received 24 August 2007/ Returned for modification 1 October 2007/ Accepted 19 November 2007

Therapy with nucleoside reverse transcriptase inhibitors (NRTIs) can be associated with mitochondrial toxicity. In vitro studies have been used to predict the predisposition for and characterize the mechanisms causing mitochondrial toxicity. Entecavir (ETV) is an approved deoxyguanosine nucleoside for the treatment of chronic hepatitis B virus (HBV) infection that exhibits potent activity against viral reverse transcriptase. We assessed the potential for mitochondrial toxicity of ETV in long-term cultures of HepG2 hepatoma cells by measuring mitochondrial function (through lactate secretion), levels of mitochondrial DNA (mtDNA), and levels of mitochondrial proteins COX II and COX IV. Furthermore, we tested the activity of ETV-triphosphate (ETV-TP) against mitochondrial DNA polymerase {gamma} (Pol {gamma}) in vitro. ETV concentrations as high as 100 times the maximal clinical exposure (Cmax) did not affect cell proliferation, levels of lactate, mitochondrial DNA, or mitochondrial proteins throughout the 15-day culture. The lack of mitochondrial toxicity was consistent with the finding that ETV-TP was not recognized by mitochondrial DNA Pol {gamma} and failed to be incorporated into DNA or inhibit the polymerase assay at the highest levels tested, 300 µM. Combinations of ETV with each of the other HBV NRTI antivirals, adefovir, tenofovir, and lamivudine at 10 times their respective Cmax levels also failed to result in cellular or mitochondrial toxicity. In summary, cell culture and enzymatic studies yielded no evidence that would predict mitochondrial toxicity of ETV at exposure levels in excess of those expected to be achieved clinically.

* Corresponding author. Mailing address: Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492. Phone: (203) 677-7846. Fax: (203) 677-6088. E-mail: daniel.tenney{at}bms.com

{triangledown} Published ahead of print on 3 December 2007.

{dagger} Present address: Ardea Biosciences, 3300 Hyland Ave., Costa Mesa, CA 92626.

Antimicrobial Agents and Chemotherapy, February 2008, p. 598-605, Vol. 52, No. 2
0066-4804/08/$08.00+0     doi:10.1128/AAC.01122-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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