Potential impairment of monensin CYP3A-dependent liver metabolism by macrolide antimicrobials

Abstract

Traditional macrolide antimicrobials are well-known inhibitors of cytochrome P4503A (CYP3A) isozymes in cattle liver. Monensin (MON), an ionophore antibiotic with a narrow safety margin, is detoxified via CYP3A. Consequently, the incompatibility between ionophores and certain macrolides is well-known in livestock animals. We hypothesized that this metabolic interaction could also occur with more recently introduced macrolides, such as tilmicosin (TIL), tulathromycin (TUL), and gamithromycin (GAM). This study aimed to evaluate the effects of TIL, TUL, GAM and MON on the CYP3A-dependent metabolism in cattle liver microsomes, and to assess the influence of the mentioned macrolides on the metabolism of MON itself. Testosterone 6β-hydroxylase (TST 6β-OH) activity(a marker of CYP3A-dependent metabolism) was assayed in liver microsomes from steers (n=4) incubated either in absence (controls) or presence of 25 and 125 µM of TIL, TUL, or GAM alone or in combination with 250 µM of MON. Triacetyloleandomycin (TAO) was used as the reference macrolide drug. MON (0.72 µM) metabolism was studied both in the absence and presence of all the aforementioned macrolides (5 µM). Incubated samples were analyzed by HPLC with UV detection (testosterone 6β-hydroxylase) or MS/MS detection (MON metabolism). An 81% inhibition (p<0.05) of TST 6β-OH activity was observed only in presence of TAO at both concentrations assayed. The rate of MON metabolism in control incubations was 19.4±1.6 pmol/min.mg. TAO inhibited MON liver metabolism (76%, p<0.05). Only minor inhibition (16-25%, p<0.05) of the ionophore metabolism was observed in the presence of TIL, TUL and GAM. These observations indicate that “new” macrolides (TIL, TUL and GAM) could not be considered as CYP3A inhibitors. Similarly, their potential impairment of MON hepatic metabolism would be of minor clinical relevance. Therefore, the concurrent administration of the novel macrolide antimicrobials with MON would be safe in cattle.