title: In vitro drug metabolism by human carboxylesterase 1: focus on angiotensin-converting enzyme inhibitors.
abstract: Carboxylesterase 1 (CES1) is the major hydrolase in human liver. The enzyme is involved in the metabolism of several important therapeutic agents, drugs of abuse, and endogenous compounds. However, no studies have described the role of human CES1 in the activation of two commonly prescribed angiotensin-converting enzyme inhibitors: enalapril and ramipril. Here, we studied recombinant human CES1- and CES2-mediated hydrolytic activation of the prodrug esters enalapril and ramipril, compared with the activation of the known substrate trandolapril. Enalapril, ramipril, and trandolapril were readily hydrolyzed by CES1, but not by CES2. Ramipril and trandolapril exhibited Michaelis-Menten kinetics, while enalapril demonstrated substrate inhibition kinetics. Intrinsic clearances were 1.061, 0.360, and 0.02 ml/min/mg protein for ramipril, trandolapril, and enalapril, respectively. Additionally, we screened a panel of therapeutic drugs and drugs of abuse to assess their inhibition of the hydrolysis of p-nitrophenyl acetate by recombinant CES1 and human liver microsomes. The screening assay confirmed several known inhibitors of CES1 and identified two previously unreported inhibitors: the dihydropyridine calcium antagonist, isradipine, and the immunosuppressive agent, tacrolimus. CES1 plays a role in the metabolism of several drugs used in the treatment of common conditions, including hypertension, congestive heart failure, and diabetes mellitus; thus, there is a potential for clinically relevant drug-drug interactions. The findings in the present study may contribute to the prediction of such interactions in humans, thus opening up possibilities for safer drug treatments.
authors.affiliation: Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark (R.T., K.L.); and Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen University Hospital, Roskilde, Denmark (H.B.R.).
authors.forename: Ragnar
authors.initials: R
authors.lastname: Thomsen
authors.forename: Henrik B
authors.initials: HB
authors.lastname: Rasmussen
authors.forename: Kristian
authors.initials: K
authors.lastname: Linnet
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000378:metabolism*; D043182:Carboxylesterase / Q000378:metabolism; D002265:Carboxylic Ester Hydrolases / Q000378:metabolism*; D004110:Diltiazem / Q000378:metabolism; D004347:Drug Interactions / Q000502:physiology; D004656:Enalapril / Q000378:metabolism; D004952:Esters / Q000378:metabolism; D006801:Humans; D006868:Hydrolysis; D008658:Inactivation, Metabolic / Q000502:physiology*; D007211:Indoles / Q000378:metabolism; D007700:Kinetics; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D009596:Nitrophenols / Q000378:metabolism; D011355:Prodrugs / Q000378:metabolism; D017257:Ramipril / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D014700:Verapamil / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D004952:Esters; D007211:Indoles; D009596:Nitrophenols; D011355:Prodrugs; D011994:Recombinant Proteins; C052035:trandolapril; D004656:Enalapril; C008642:4-nitrophenyl acetate; D014700:Verapamil; D002265:Carboxylic Ester Hydrolases; C474609:CES1 protein, human; C517204:CES2 protein, human; D043182:Carboxylesterase; D004110:Diltiazem; D017257:Ramipril