Studies on the toxic interaction between monensin and tiamulin in rats: Effects on P450 activities

Studies were carried out to investigate the effects of monensin and tiamuli n, and the simultaneous administration of both compounds on microsomal enzy mes in rats. In Phase I of the experiments the effects of monensin and tiam ulin were studied separately (monensin 10, 30, and 50 mg/kg or tiamulin 40, 120, and 200 mg/kg body weight, respectively), while in Phase II the two c ompounds were administered simultaneously (monensin 10 mg/kg and tiamulin 4 0 mg/kg b.w., respectively). When monensin was administered by itself, it e xerted no significant effect on microsomal liver enzymes. In a few cases, s light inhibition of certain enzyme activities was seen. Tiamulin provoked a dose-dependent hepatic enzyme induction. The combined administration of mo nensin and tiamulin at low doses (10 and 40 mg/kg, respectively) resulted i n marked elevation of P450-related enzyme activities. The enzyme induction was more pronounced in females than in males. The results suggest that the simultaneous administration of tiamulin may influence the biotransformation of monensin, possibly increasing the amount of reactive metabolite(s) of t he ionophore antibiotic.