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School of Pharmaceutical Sciences, Kitasato University, Shirokane, Minato-ku, Tokyo, Japan
Clinical studies have revealed that plasma concentrations of midazolam
after oral administration are greatly increased by coadministration of
erythromycin and clarithromycin, whereas azithromycin has little effect on
midazolam concentrations. Several macrolide antibiotics are known to be
mechanism-based inhibitors of CYP3A, a cytochrome P450 isoform responsible for
midazolam hydroxylation. The aim of the present study was to quantitatively
predict in vivo drug interactions in humans involving macrolide antibiotics
with different inhibitory potencies based on in vitro studies. 
- and
4-Hydroxylation of midazolam by human liver microsomes were evaluated as
CYP3A-mediated metabolic reactions, and the effect of preincubation with
macrolides was examined. The hydroxylation of midazolam was inhibited in a
time- and concentration-dependent manner following preincubation with
macrolides in the presence of NADPH, whereas almost no inhibition was observed
without preincubation. The kinetic parameters for enzyme inactivation
(K'app and kinact) involved in
midazolam -hydroxylation were 12.6 µM and 0.0240
min–1, respectively, for erythromycin, 41.4 µM
and 0.0423 min–1, respectively, for
clarithromycin, and 623 µM and 0.0158 min–1,
respectively, for azithromycin. Similar results were obtained for the
4-hydroxylation pathway. These parameters and the reported pharmacokinetic
parameters of midazolam and macrolides were then used to simulate in vivo
interactions based on a physiological flow model. The area under the
concentration-time curve (AUC) of midazolam after oral administration was
predicted to increase 2.9- or 3.0-fold following pretreatment with
erythromycin (500 mg t.i.d. for 5 or 6 days, respectively) and 2.1- or
2.5-fold by clarithromycin (250 mg b.i.d. for 5 days or 500 mg b.i.d. for 7
days, respectively), whereas azithromycin (500 mg o.d. for 3 days) was
predicted to have little effect on midazolam AUC. These results agreed well
with the reported in vivo observations.
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