RT Journal Article SR Electronic T1 PREDICTION OF THE IN VIVO INTERACTION BETWEEN MIDAZOLAM AND MACROLIDES BASED ON IN VITRO STUDIES USING HUMAN LIVER MICROSOMES JF Drug Metabolism and Disposition JO Drug Metab Dispos FD American Society for Pharmacology and Experimental Therapeutics SP 945 OP 954 DO 10.1124/dmd.31.7.945 VO 31 IS 7 A1 Kiyomi Ito A1 Kanako Ogihara A1 Shin-ichi Kanamitsu A1 Tomoo Itoh YR 2003 UL http://dmd.aspetjournals.org/content/31/7/945.abstract AB 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. α- 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 α-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. The American Society for Pharmacology and Experimental Therapeutics