Lack of effect of streptogramins on hepatic drug metabolism enzymes in the rat.
Male Sprague-Dawley rats were treated with streptogramin derivatives (RP 7293, RP 54476, RP 57669, and RP 59500) or with the macrolide troleandomycin. Liver cytosol and microsomes were prepared, and the in vitro transformation of several model substrates studied. Furthermore, total and complexed microsomal cytochrome P-450 levels were compared. Hepatic cytochrome P-450 metabolite complexes were detected 4 days after troleandomycin treatment (500 mg/kg/day po), whereas such effects were not observed with po RP 7293 (500 mg/kg/day, 4 days) or with iv RP 54476 (12 mg/kg/day, 7 days), RP 57669 (6 mg/kg/day, 7 days), or RP 59500 (6 and 18 mg/kg/day, 7 days). The administration of troleandomycin resulted in statistically significant increases in liver weight (+20%), microsomal protein (+70%), total cytochrome P-450 (+187%), and cytosolic glutathione S-transferase activity (+32%). The activities of aniline hydroxylase, aminopyrine N-demethylase, and the high and low phases of 7-ethoxyresorufin O-deethylase were markedly decreased by 36% to 56%. In contrast, none of these hepatic parameters was changed significantly after administration of each streptogramin. These results suggest that streptogramins have not, in contrast to many commonly used macrolide antibiotics, had potent or specific effects on hepatic drug metabolizing enzymes in rats.
Rhône-Poulenc Rorer Recherche et Développement, Département de Biodynamique, Antony, France.
M R
MR
Martinet
Y
Y
Vedrine
V
V
Piguet
A
A
Frydman
D015660:7-Alkoxycoumarin O-Dealkylase / Q000032:analysis; D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000032:analysis; D005982:Glutathione Transferase / Q000032:analysis; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains; D014769:Virginiamycin / Q000494:pharmacology*
D014769:Virginiamycin; D003577:Cytochrome P-450 Enzyme System; D015660:7-Alkoxycoumarin O-Dealkylase; D005982:Glutathione Transferase