RT Journal Article
SR Electronic
T1 In Vitro Hydrolysis and Transesterification of CDP323, an <em>α</em>4<em>β</em>1/<em>α</em>4<em>β</em>7 Integrin Antagonist Ester Prodrug
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 153
OP 161
DO 10.1124/dmd.113.054049
VO 42
IS 1
A1 Hugues Chanteux
A1 Maria Rosa
A1 Claude Delatour
A1 Chandra Prakash
A1 Steven Smith
A1 Jean-Marie Nicolas
YR 2014
UL http://dmd.aspetjournals.org/content/42/1/153.abstract
AB We identified the enzyme(s) involved in the hydrolysis of the ethyl ester prodrug CDP323 (C28H29BrN403) and characterized its transesterification in the presence of ethanol with special emphasis on the risks of drug-drug interaction. The hydrolysis of CDP323 was evaluated in vitro using human liver and intestinal microsomes and recombinant human carboxylesterases (hCES1 and 2) and was shown to be approximately 20-fold higher in human liver microsomes when compared with human intestinal microsomes and in hCES1 when compared with hCES2. Nonspecific inhibitors of carboxylesterases significantly inhibited the hydrolysis of CDP323 (&gt;80% inhibition) while specific inhibitors of CES2, acetylcholine esterase, arylesterase, and butyrylcholinesterase did not impair the hydrolysis reaction. The effect of ethanol on the kinetic parameters for hydrolysis was investigated, demonstrating that at high concentration (2%), Michaelis-Menten constant (Km), maximum velocity (Vmax), and intrinsic clearance (CLint) for the formation of the hydrolyzed product were decreased (∼40%). The use of deuterated ethanol allowed more mechanistic investigations of the transesterification mechanism and showed that the intrinsic clearance based on parent loss was not impaired in the presence of alcohol. Overall, our data demonstrate that CDP323 is mainly hydrolyzed by hCES1 and is prone to transesterification in the presence of ethanol. Transesterification mechanisms compete with hydrolysis without impairing the overall clearance of the ester prodrug. Based on in vitro results, the risk of a clinically significant drug-drug interaction with ethanol is anticipated to be low.