Specific drug binding to rat liver cytochrome P-450 isozymes induced by pregnenolone-16 alpha-carbonitrile and macrolide antibiotics. Implications for drug interactions.
Clinical interactions of macrolides with various drugs lead to elimination impairment, increase of plasma concentration and overdose-like effects, resulting from modifications of their metabolism. Previous studies have shown that treatment of rats by the macrolide antibiotics of the oleandomycin and erythromycin series lead to the induction of an hepatic cytochrome P-450 which is implicated into their own metabolism. We have characterized PCN or macrolides induced cytochromes P-450 by their specific ability to interact with macrolide derivatives and, using the cytochrome P-450 spectral binding assays, we have shown that some compounds, implicated in drug interaction with macrolides, interact preferentially with the same cytochromes. This strongly suggests that specific blockage of cytochrome P-450 IIIA1 family by macrolides, is responsible for these drug interactions and that these interactions can be predicted easily by simple in vitro tests such as those described herein.
Sartori
E
E
Université René Descartes, UA 400 CNRS, Laboratoire de Chimie et Biochimie, Paris, France.
Delaforge
M
M
D000818:Animals; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004790:Enzyme Induction / Q000187:drug effects; D004878:Ergotamine; D004879:Ergotamines / Q000378:metabolism; D004917:Erythromycin / Q000031:analogs & derivatives / Q000494:pharmacology; D004997:Ethinyl Estradiol / Q000378:metabolism; D005036:Ethylmorphine / Q000378:metabolism; D005292:Ferricyanides / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009640:Norethindrone / Q000378:metabolism; D011239:Prednisolone / Q000378:metabolism; D011241:Prednisone / Q000378:metabolism; D011285:Pregnenolone Carbonitrile / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013053:Spectrophotometry; D013806:Theophylline / Q000378:metabolism
D000900:Anti-Bacterial Agents; D004879:Ergotamines; D005292:Ferricyanides; D007527:Isoenzymes; C007931:hexacyanoferrate III; D011285:Pregnenolone Carbonitrile; D004997:Ethinyl Estradiol; C060074:erythralosamine-2',3-diacetate; D004917:Erythromycin; D003577:Cytochrome P-450 Enzyme System; D011239:Prednisolone; D013806:Theophylline; D004878:Ergotamine; D005036:Ethylmorphine; D009640:Norethindrone; D011241:Prednisone