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Six-month repeated dose toxicity of orally administered metacavir in rhesus monkeys
Zheng-li Chen1, Wen Zeng, An-chun Cheng
1Engineering and Techonlogy Center for Laboratory Animals of Sichuan Agricultural University, Ya-an 625014, China.
Objective:
To explore the toxicities of metacavir, a novel deoxyguanosine analog with an anti-hepatitis B virus (HBV) potential, in a 6-month repeated dosing in rhesus monkeys.
Methods:
Rhesus monkeys were divided into four groups with eight animals in each group. Metacavir or blank vehicles were given for up to 6-month, and then the animals were euthanized 3 and 6 months later. Biochemical and hematological parameters, general symptoms, ECG, serum antibodies, and tissue pathology were observed and recorded.
Results:
No biologically meaningful influences on body weight, body temperature, ocular examination, ECG, and organ weight were observed. The main toxic effects included: obvious gastrointestinal toxicities were observed in metacavir 200 mg/kg group, in which animals experienced vomiting and decrease in food consumption. Along with the increase of dosing times, animals gradually tolerated the drug and all these effects gradually abated. Hematological damages included increased damage of red blood cells, decrease of red blood cell count and hemoglobin levels. Hepatic functions were also damaged at certain levels, including the decreases in total protein, albumin, and glucose and the fatty degeneration in hepatocytes. Mild stenosis and exfoliation of gastric and duodenal mucosa was observed. The mild necrosis and exfoliation of renal tubules epithelia was found 6 months after the start of dosing. All these toxic effects were dose dependent.
Conclusion:
The main target organs of the toxic effects of metacavir are gastrointestinal tract, liver, blood, and kidneys. The no-observed-adverse-effect-level (NOAEL) of metacavir for rhesus monkey were considered to be 50 mg/kg/day.
Insights
Metacavir, an anti-hepatitis B virus drug, showed dose-dependent toxicities in rhesus monkeys, primarily affecting the gastrointestinal tract, liver, blood, and kidneys. The no-observed-adverse-effect-level was determined to be 50 mg/kg/day.
Area of Science:
- Pharmacology
- Toxicology
- Hepatitis B Virus Research
Background:
- Hepatitis B virus (HBV) infection is a global health concern.
- Novel antiviral agents are crucial for managing chronic HBV.
- Metacavir is a deoxyguanosine analog with potential anti-HBV activity.
Purpose of the Study:
- To evaluate the toxicological profile of metacavir.
- To determine the safety of repeated dosing of metacavir in a preclinical model.
- To identify target organs for metacavir-induced toxicity.
Main Methods:
- A 6-month repeated dosing study was conducted in rhesus monkeys.
- Animals were divided into four groups, receiving metacavir or vehicle.
- Comprehensive assessments included biochemical, hematological, clinical, and histopathological evaluations.
Main Results:
- Gastrointestinal toxicities (vomiting, decreased appetite) were observed at higher doses but abated over time.
- Hematological effects included damage to red blood cells and decreased hemoglobin.
- Liver function was impaired, with decreased protein, albumin, and glucose, and fatty changes in hepatocytes. Renal tubule damage was also noted.
Conclusions:
- The primary target organs for metacavir toxicity are the gastrointestinal tract, liver, blood, and kidneys.
- Toxic effects were dose-dependent.
- The no-observed-adverse-effect-level (NOAEL) for metacavir in rhesus monkeys was established at 50 mg/kg/day.
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