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Metronidazole hprt mutation induction in sheep and the relationship with its elimination rate
P Ostrosky-Wegman1, I L Asseff, P Santiago
1Instituto de Investigaciones Biomédicas, UNAM, México D.F., Mexico.
Abstract:
Gene mutations at the hprt locus were determined in peripheral blood lymphocytes from nine sheep treated with metronidazole (MZ) at therapeutic doses for amebiasis. Pharmacokinetic studies were also carried out, including the calculation of the apparent first-order elimination rate constant (K10) and the steady state concentration of MZ in plasma. Three sheep showed an increase of variant frequencies (Vf) at the hprt locus. A proportional relationship was found between the highest Vf and the highest steady state in plasma, and an inverse relationship between Vf and K10. The finding that the animals with the lowest elimination rates of MZ had increased gene mutations indicates that differences in pharmacokinetics constitute one potential mechanism of genotoxic susceptibility.
Insights
Metronidazole treatment in sheep can increase gene mutations. Slower drug elimination and higher drug levels in the blood correlate with increased genetic damage, suggesting pharmacokinetic differences influence genotoxicity.
Area of Science:
- Pharmacology and Toxicology
- Genetics and Molecular Biology
- Veterinary Medicine
Background:
- Metronidazole is a common antimicrobial agent used to treat amebiasis.
- Understanding the genotoxic potential of drugs is crucial for patient safety.
- Individual variability in drug metabolism can affect toxicity.
Purpose of the Study:
- To investigate gene mutations at the hypoxanthine-guanine phosphoribosyltransferase (hprt) locus in sheep treated with metronidazole.
- To explore the relationship between metronidazole pharmacokinetics and genotoxicity.
- To identify potential mechanisms of genotoxic susceptibility.
Main Methods:
- Determined gene mutations at the hprt locus in peripheral blood lymphocytes of nine sheep.
- Conducted pharmacokinetic studies, calculating elimination rate constant (K10) and steady-state plasma concentration of metronidazole.
- Analyzed variant frequencies (Vf) in relation to pharmacokinetic parameters.
Main Results:
- Three out of nine sheep exhibited increased variant frequencies (Vf) at the hprt locus.
- A positive correlation was observed between the highest Vf and the highest steady-state plasma concentration of metronidazole.
- An inverse correlation was found between Vf and the elimination rate constant (K10).
Conclusions:
- Differences in drug elimination rates influence metronidazole-induced genotoxicity in sheep.
- Animals with lower metronidazole elimination rates showed increased gene mutations.
- Pharmacokinetic variability is a potential mechanism underlying genotoxic susceptibility to metronidazole.