METRONIDAZOLE HPRT MUTATION-INDUCTION IN SHEEP AND THE RELATIONSHIP WITH ITS ELIMINATION

Gene mutations at the hprt locus were determined in peripheral blood l ymphocytes from nine sheep treated with metronidazole (MZ) at therapeu tic doses for amebiasis. Pharmacokinetic studies were also carried out , including the calculation of the apparent first-order elimination ra te constant (K-10) and the steady state concentration of MZ in plasma. Three sheep showed an increase of variant frequencies (Vf) at the hpr t locus. A proportional relationship was found between the highest Vf and the highest steady state in plasma, and an inverse relationship be tween Vf and K-10. The finding that the animals with the lowest elimin ation rates of MZ had increased gene mutations indicates that differen ces in pharmacokinetics constitute one potential mechanism of genotoxi c susceptibility.