3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 23-26 October 2001, Athens, Greece

EVALUATION OF MITOCHONDRIAL EFFECTS IN TENOFOVIR DISIPROXIL FUMARATE-TREATED RATS AND PRIMATES

Antiviral Therapy 2001; 6(Suppl. 4):28 (abstract no. 37)

G Biesecker, S Karimi, J Desjardins, D Meyer, B Abbott and F Richardson
Gilead Sciences Inc., Boulder, Col., USA

The HIV reverse transcriptase (RT) inhibitor tenofovir disiproxil fumarate (DF) was evaluated for possible interference with mitochondrial function. Certain nucleoside RT inhibitors (NRTIs) can reduce mitochondria number or respiratory enzyme content and can produce muscle injury in both animals and human subjects. Rats and primates were treated by oral gavage with the NRTI tenofovir DF, and the mitochondrial enzymes cytochrome C oxidase and citrate synthase were assayed. In rats (six per group) treated for 28 days with 300 mg/kg tenofovir DF the cytochrome C oxidase enzyme levels (U/mg protein) were unchanged versus control, respectively, in liver (37.4 versus 34.8), kidney (19.4 versus 37.4) and skeletal muscle (7.0 versus 14.5); citrate synthase enzyme levels (μmol CoA/min/mg) were also unchanged versus control in liver (0.080 versus 0.071), kidney (0.23 versus 0.20) and skeletal muscle (0.17 versus 0.23). In rhesus monkeys (six per group) treated with 30 mg/kg and 250 mg/kg tenofovir DF for 56 days the cytochrome C oxidase enzyme levels, respectively, were unchanged versus control in liver (9.9 and 8.1 versus 8.9), kidney (28.8 and 33.2 versus 24.4), skeletal muscle (6.4 and 12.9 versus 12.0) and cardiac muscle (75.6 and 46.4 versus 66.1); citrate synthase levels were also unchanged in liver (0.042 and 0.057 versus 0.048), kidney (0.31 and 0.27 versus 0.23), skeletal muscle (0.12 and 0.10 versus 0.14) and cardiac muscle (0.96 and 0.91 versus 0.79). Mitochondrial DNA content in tissue was measured by quantitative PCR of the mitochondrial cytochrome b gene/genomic actin gene ratio.

Mitochondrial DNA content from treated rats was unchanged versus control in liver (8.4 versus 9.1), kidney (4.7 versus 5.1) and skeletal muscle (14.0 versus 8.3), although variation between animals in the same treatment group was observed. Mitochondrial DNA content from treated primates was also unchanged from control. In summary, treatment with tenofovir DF did not effect mitochondrial DNA content, nor did treatment effect the level of mitochondrial enzymes, and there was no evidence of tissue pathology associated with mitochondrial injury at any dose level for tenofovir DF.

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