Cytochrome P-450 complex formation in rat liver by the antibiotic tiamulin.
Tiamulin is a semisynthetic diterpene antibiotic frequently used in farm animals. The drug has been shown to produce clinically important--often lethal--interactions with other compounds. It has been suggested that this is caused by a selective inhibition of oxidative drug metabolism via the formation of a cytochrome P-450 metabolic intermediate complex. In the present study, rats were treated orally for 6 days with tiamulin at two different doses: 40 and 226 mg/kg of body weight. For comparison, another group received 300 mg of triacetyloleandomycin (TAO) per kg, which is equivalent to the 226-mg/kg tiamulin group. Subsequently, microsomal P-450 contents, P-450 enzyme activities, metabolic intermediate complex spectra, and P-450 apoprotein concentrations were assessed. In addition, effects on individual microsomal P-450 activities were studied in control microsomes at different tiamulin and substrate concentrations. In the rats treated with tiamulin, a dose-dependent complex formation as evidenced by its absorption spectrum and an increase in cytochrome P-4503A1/2 contents as assessed by Western blotting (immunoblotting) were found. The effects were comparable to those of TAO. Tiamulin induced microsomal P-450 content, testosterone 6 beta-hydroxylation rate, erythromycin N-demethylation rate, and the ethoxyresorufin O-deethylation activity. Other activities were not affected or decreased. When tiamulin was added to microsomes of control rats, the testosterone 6 beta-hydroxylation rate and the erythromycin N-demethylation were strongly inhibited. It is concluded that tiamulin is a potent and selective inducer-inhibitor of cytochrome P-450. Though not belonging to the macrolides, the compound produces an effect on P-450 similar to those of TAO and related compounds.
Witkamp
R F
RF
Department of Veterinary Basic Sciences, Utrecht University, Netherlands. r.witkamp@vfft.dgk.ruu.nl
Nijmeijer
S M
SM
van Miert
A S
AS
D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D001059:Apoproteins / Q000737:chemistry / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000187:drug effects* / Q000378:metabolism* / Q000494:pharmacology; D004224:Diterpenes / Q000494:pharmacology; D004347:Drug Interactions; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D013053:Spectrophotometry; D014217:Troleandomycin / Q000493:pharmacokinetics / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001059:Apoproteins; D004224:Diterpenes; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; C014224:tiamulin