PIII-69Inhibitory potency of clarithromycin towards CYP3As

Abstract

BACKGROUND/AIMS Drug-drug interactions observed in patients and involving clarithromycin are mostly explained through inhibition of CYP3As. The objective of our study was to characterize further the inhibitory potency of clarithromycin against CYP3As. METHODS In vitro inhibition studies were conducted with human liver microsomes (HLM) and microsomes from baculovirus-expressed human recombinant CYP3A4 (rCYP3A4) or CYP3A5 (rCYP3A5), with or without CYP b5. Experiments were initiated by a preincubation period (0–60min) of clarithromycin (0–70μM) followed by incubation of domperidone (200 or 300μM) or midazolam (25, 50 or 300μM) for 45 or 20 min, respectively. Formation rate of domperidone major hydroxylated metabolite (M3) or 1- and 4OH-midazolam were monitored by HPLC with fluorescence and UV detection, respectively. RESULTS Clarithromycin at concentrations as high as 70μM caused very limited inhibition of domperidone and midazolam in HLM. Percent inhibitions from clarithromycin 70μM were as follows: (See Table) Enzyme Sources M3-domperidone 1OH-midazolam 4OH-midazolam HLM 10% 27% 5% rCYP3A4 61% 12% 25% rCYP3A4+CYPb5 9% 0% 0% rCYP3A5 45% 27% 3% rCYP3A5+CYPb5 18% 15% 5% CONCLUSIONS Our results suggest that CYP3As play a minor role in in vivo interactions involving clarithromycin. CYP b5 appears to be a major determinant of rCYP3A activity. We propose that the underlying mechanism of drug-drug interaction with clarithromycin should be revisited. Clinical Pharmacology & Therapeutics (2005) 79, P77–P77; doi: 10.1016/j.clpt.2005.12.277