THE ANTIBIOTIC TIAMULIN IS A POTENT INDUCER AND INHIBITOR OF CYTOCHROME P4503A VIA THE FORMATION OF A STABLE METABOLIC INTERMEDIATE COMPLEX- STUDIES IN PRIMARY HEPATOCYTE CULTURES AND LIVER-MICROSOMES OF THE PIG

Tiamulin is a semisynthetic antibiotic frequently used in agricultural animals, The drug has been shown to produce clinically important-ofte n lethal-interactions with other compounds that are simultaneously adm inistered, To explain this, it has been suggested that tiamulin select ively inhibits oxidative drug metabolism via the formation of a cytoch rome P450 metabolic intermediate complex, The aim of the present study was to provide further support for this hypothesis, When hepatic micr osomes and cultured primary pig hepatocytes were incubated with tiamul in, a maximum in the absorbance spectrum at 455 nm was observed, which disappeared after adding KFe(CN)(6). When hepatocytes were incubated with tiamulin for 72 hr, cytochrome P450 content and cytochrome P4503A apoprotein levels were increased, Tiamulin strongly inhibited and con centration dependently inhibited the hydroxylation rate of testosteron e at the 6 beta-position in both microsomes and hepatocytes, and the m icrosomal N-demethylation rate of ethylmorphine, Other testosterone hy droxylations were inhibited to a lesser extent or not affected, The re lative inhibition of the hydroxylation of testosterone at the 6 beta-p osition was more pronounced in microsomes from rifampicin- and triacet yloleandomycin-treated pigs. The results indicate that cytochrome P450 complex formation can at least partly explain the interactions observ ed with tiamulin, Tiamulin seems to be a strong, probably selective, i nhibitor of the cytochrome P4503A subfamily and an interesting tool fo r further research.