HIGHLY SELECTIVE INHIBITION OF HUMAN CYP3A IN VITRO BY AZAMULIN AND EVIDENCE THAT INHIBITION IS IRREVERSIBLE

Abstract

Azamulin [14-O-(5-(2-amino-1,3,4-triazolyl)thioacetyl)-dihydromutilin] is an azole derivative of the pleuromutilin class of antiinfectives. We tested the inhibition potency of azamulin toward 18 cytochromes P450 using human liver microsomes or microsomes from insect cells expressing single isoforms. In a competitive inhibition model, IC₅₀ values for CYP3A (0.03–0.24 μM) were at least 100-fold lower than all other non-CYP3A enzymes except CYP2J2 (∼50-fold lower). The IC₅₀ value with heterologously expressed CYP3A4 was 15-fold and 13-fold less than those of CYP3A5 and CYP3A7, respectively. The reference inhibitor ketoconazole was less selective and exhibited potent inhibition (IC₅₀ values 300 μM. Azamulin represents an important new chemical tool for use in characterizing the contribution of CYP3A to the metabolism of xenobiotics.