Interaction of dexloxiglumide, a cholecystokinin type-1 receptor antagonist, with human cytochromes P450

Dexloxiglumide (DEX) is a cholecystokinin type‐1 receptor antagonist under development for the treatment of constipation‐predominant irritable bowel syndrome. Studies of the potential interaction of DEX with human cytochromes P450 (CYPs) were conducted in vitro. DEX (300µM), both with and without a 15‐min pre‐incubation, was incubated with pooled human liver microsomes and substrates selective for each of eight CYPs. This resulted in >30% inhibition of tolbutamide 4‐methyl‐hydroxylase (CYP2C9/10) and lauric acid 11‐hydroxylase (CYP2E1) activities. Mean Ki (SD) for CYP2C9/10 and CYP2E1 were 69.0 (24.3) and 426 (60)µM, respectively. Incubations of [14C]DEX with pooled human liver microsomes produced one major phase I metabolic fraction, with Vmax=131 pmol/min/mg protein and Km=23.7µM. Further incubations with (i) liver microsomes from 16 individual donors (correlation analysis), (ii) Supersomes™ and (iii) selective chemical inhibitors, implicated CYP3A4/5, CYP2B6 and CYP2C9 in the formation of this component. Thus, DEX interacts with CYP2C9 both as inhibitor (Ki=69.0µM) and as substrate in vitro. However, based on the maximum concentration (27µM) after repeated oral doses of 200mg t.i.d. and the unbound fraction (0.03) of DEX in human plasma, no clinically relevant metabolic interactions with other CYP substrates are predicted. Copyright © 2004 John Wiley & Sons, Ltd.