Studies on the cytochrome P450 (CYP)-mediated metabolic properties of miocamycin: evaluation of the possibility of a metabolic intermediate complex formation with CYP, and identification of the human CYP isoforms.
Some macrolide antibiotics cause clinical drug interactions, resulting in altered metabolism of concomitantly administered drugs, via the formation of a metabolic intermediate (MI) complex with cytochrome P450 (CYP), or competitive inhibition of CYP. In this study, the possibility of MI complex formation by miocamycin (MOM) was assessed first. CYP contents and activities in rat liver microsomes were not affected and there were no detectable MI complexes after administration of MOM for either 3 or 10 days to rats. Furthermore, MOM did not form MI complexes in vitro even with microsomes from humans or dexamethasone-pretreated rats. Second, in vitro studies were conducted to identify the human CYP isoforms involved in four 14-hydroxylation reactions in the MOM metabolic pathway. The results showed that it was most likely CYP3A4 involved in the hydroxylations: 1) each hydroxylation in human liver microsomes from 10 different donors strongly correlated with testosterone 6 beta-hydroxylation; 2) each hydroxylation was essentially inhibited by ketoconazole and troleandomycin; 3) only cDNA-expressed CYP3A4 and CYP3A5 catalyzed the hydroxylations, and the activities of CYP3A5 were below 5% of those of CYP3A4; and 4) the apparent K(M) values obtained with native human liver microsomes were comparable with those obtained with cDNA-expressed CYP3A4. In conclusion, MOM is not an inhibitor of CYP via the formation of an MI complex. Moreover, CYP3A4 is mainly responsible for catalyzing the hydroxylation of MOM metabolites. Because CYP3A4 is the most abundant form of CYP in the liver and intestine, this isoform probably accounts for the majority of drug-MOM interactions observed in clinical practice.
Kasahara
M
M
Pharmacokinetics Department, Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Yokohama, Japan.
Suzuki
H
H
Komiya
I
I
D000815:Aniline Hydroxylase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics*; D002851:Chromatography, High Pressure Liquid; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006900:Hydroxylation; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D015644:Miocamycin / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012044:Regression Analysis; D013739:Testosterone / Q000378:metabolism
D000900:Anti-Bacterial Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D015644:Miocamycin; D013739:Testosterone; D003577:Cytochrome P-450 Enzyme System; D000815:Aniline Hydroxylase; D019363:Cytochrome P-450 CYP1A1