Metabolism of dihydroergotamine by a cytochrome P-450 similar to that involved in the metabolism of macrolide antibiotics.
1. Previous studies have shown that the macrolide antibiotics, such as oleandomycin and erythromycin, enhance their own transformation into a stable metabolite-cytochrome P-450 complex, thus impairing monooxygenase activity. This cytochrome P-450 induced by macrolides is similar to the major form induced in rats by pregnenolone-16 alpha-carbonitrile (PCN) (III A1 isozyme). 2. The cytochrome P-450 isozyme induced in rats by PCN or macrolide antibiotics bound dihydroergotamine (DHE) with high affinity and was also capable of metabolizing the drug. However, phenobarbital administration enhanced the metabolism of DHE to a greater extent than would be expected from the levels of the PB-PCNE isoenzyme, indicating that other cytochrome P-450 proteins may also be involved in DHE metabolism. 3. DHE metabolism was inhibited by macrolide antibiotics both ex vivo and in vitro. The metabolite-cytochrome P-450 complex formed by the antibiotics impairs the metabolism of DHE, so that when the complex is dissociated the metabolic activity is restored. These findings explain the observed clinical interactions between macrolides and other drugs, and such an approach may prove useful in their prediction.
Delaforge
M
M
UA 400 CNRS, Université René Descartes, Paris, France.
Rivière
R
R
Sartori
E
E
Doignon
J L
JL
Grognet
J M
JM
D000818:Animals; D001711:Biotransformation; D002851:Chromatography, High Pressure Liquid; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004087:Dihydroergotamine / Q000378:metabolism / Q000493:pharmacokinetics*; D005260:Female; D007527:Isoenzymes / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology; D010634:Phenobarbital / Q000494:pharmacology; D011285:Pregnenolone Carbonitrile / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D014217:Troleandomycin / Q000378:metabolism / Q000494:pharmacology
D007527:Isoenzymes; D011285:Pregnenolone Carbonitrile; D004087:Dihydroergotamine; D003577:Cytochrome P-450 Enzyme System; D014217:Troleandomycin; D010634:Phenobarbital