RT Journal Article
SR Electronic
T1 In Vivo Evaluation of Drug-Drug Interaction via Mechanism-Based Inhibition by Macrolide Antibiotics in Cynomolgus Monkeys
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 2127
OP 2136
DO 10.1124/dmd.109.028969
VO 37
IS 11
A1 Akihito Ogasawara
A1 Isao Negishi
A1 Kazumasa Kozakai
A1 Toshiyuki Kume
YR 2009
UL http://dmd.aspetjournals.org/content/37/11/2127.abstract
AB Irreversible inhibition, characterized as mechanism-based inhibition (MBI), of cytochrome P450 in drugs has to be avoided for their safe use. A comprehensive assessment of drug-drug interaction (DDI) potential is important during the drug discovery process. In the present study, we evaluated the effects of macrolide antibiotics, erythromycin (ERM), clarithromycin (CAM), and azithromycin (AZM), which are mechanism-based inhibitors of CYP3A, on biotransformation of midazolam (MDZ) in monkeys. These macrolides inhibited the formation of 1′-hydroxymidazolam in monkey microsomes as functions of incubation time and macrolide concentration. Furthermore, the inactivation potentials of macrolides (kinact/KI: CAM ≅ ERM > AZM) were as effective as that observed in human samples. In in vivo studies, MDZ was administered orally (1 mg/kg) without or with multiple oral dosing of macrolides (15 mg/kg, twice a day on days 1–3). On day 3, the area under the plasma concentration-time curve (AUC) of MDZ increased 7.0-, 9.9-, and 2.0-fold with ERM, CAM, and AZM, respectively, compared with MDZ alone. Furthermore, the effects of ERM and CAM on the pharmacokinetics of MDZ were also observed on the day (day 4) after completion of macrolide treatments (AUC changes: 7.3- and 7.3-fold, respectively). Because the plasma concentrations of macrolides immediately before MDZ administration on day 4 were much lower than the IC50 values for reversible CYP3A inhibition, the persistent effects may be predominantly caused by CYP3A inactivation. These results suggest that the monkey might be a suitable animal model to predict DDIs caused by MBI of CYP3A. Copyright © 2009 by The American Society for Pharmacology and Experimental Therapeutics