Investigation of drug-drug interaction via mechanism-based inhibition of cytochrome P450 3A by macrolides in dexamethasone-treated female rats

ABSTRACT The in vitro and in vivo inhibition of cytochrome P450 (CYP) 3A with mechanism‐based inhibition (MBI) by macrolides was investigated using dexamethasone‐treated female rats (DEX‐female rats). In the in vitro CYP inhibition studies using erythromycin (ERM) and clarithromycin (CAM), similar i...

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Published in:Biopharmaceutics & drug disposition 2012-05, Vol.33 (4), p.195-206
Main Authors: Kanazu, Takushi, Sato, Norihito, Kadono, Kyoko, Touchi, Akira, Takeda, Yuri, Yamaguchi, Yoshitaka, Baba, Takahiko
Format: Article
Language:English
Subjects:
Animals
Area Under Curve
Clarithromycin - pharmacology
Cytochrome P-450 CYP3A - metabolism
Cytochrome P-450 CYP3A Inhibitors
cytochrome P450 (CYP) 3A
dexamethasone
Dexamethasone - administration & dosage
Dexamethasone - pharmacology
Drug Interactions
drug-drug interaction
Erythromycin - pharmacology
Female
female rat
Humans
Male
mechanism-based inhibition
Microsomes, Liver - drug effects
Microsomes, Liver - metabolism
Midazolam - metabolism
Models, Biological
Rats
Sex Factors
Species Specificity
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Summary:ABSTRACT The in vitro and in vivo inhibition of cytochrome P450 (CYP) 3A with mechanism‐based inhibition (MBI) by macrolides was investigated using dexamethasone‐treated female rats (DEX‐female rats). In the in vitro CYP inhibition studies using erythromycin (ERM) and clarithromycin (CAM), similar inhibition responses were observed between human and DEX‐female rat liver microsomes, however, there were fewer effects in intact male rats. The ex vivo study showed that midazolam (MDZ) metabolism in liver microsomes of DEX‐female rats was reduced by ERM administration and the inhibitory effect was increased with increasing ERM doses, indicating that metabolite intermediate complex formation caused irreversible inhibition of CYP3A activity in DEX‐female rats as well as in humans. In the in vivo studies, ERM and CAM significantly increased the area under the plasma concentration–time curve of MDZ and decreased the total clearance in DEX‐female rats. It was concluded that the DDIs via MBI of CYP3A following macrolide administration in humans could be reproduced in female rats, suggesting that DEX‐female rats can serve as an in vivo model for assessing this DDI in humans. Copyright © 2012 John Wiley & Sons, Ltd.
ISSN:0142-2782
1099-081X
DOI:10.1002/bdd.1785