In vitro complex formation and inhibition of hepatic cytochrome P450 activity by different macrolides and tiamulin in goats and cattle

In humans, clinically relevant drag-drug interactions occur with some macro lide antibiotics via the formation of stable metabolic intermediate (MI) co mplexes with enzymes of the cytochrome P4503A (CYP3A) subfamily. The format ion of such complexes can result in a decreased biotransformation rate of s imultaneously administered drugs. In previous studies it was shown that the veterinary antibiotic tiamulin was also able to form a stable MI complex i n pigs and rats. In the present study the relative CYP3A inhibiting potency and MI complex formation of a series of macrolide antibiotics and tiamulin were studied in microsomal fractions of goat and cattle and in a cell-line expressing bovine CYP3A. Tiamulin and triacetyloleandomycin (TAO) were fou nd to be effective inhibitors of CYP450 activity in all systems tested. Ery thromycin and tilmicosin were found to be relatively less effective inhibit ors of CYP450 activity in microsomes, and their activity in the bovine CYP3 A4 expressing cell line was relatively weak. Tylosin was shown to be a weak inhibitor in microsomes and not in the cell line, whereas spiramycin had n o effect at all. MI-complex formation measured by spectral analysis was see n with TAO, tiamulin, erythromycin and tylosin, but not with tilmicosin and spiramycin. Although additional factors play a role in vivo, these results may explain potential drug-drug interactions and differences between relat ed compounds in this respect.