Two major forms of human carboxylesterase (CES), CES1A and CES2, dominate the pharmacokinetics of most prodrugs such\nas imidapril and irinotecan (CPT-11). Excipients, largely used as insert vehicles in formulation, have been recently reported to\naffect drug enzyme activity. The influence of excipients on the activity of CES remains undefined. In this study, the inhibitory\neffects of 25 excipients on the activities of CES1A1 and CES2 were evaluated. Imidapril and CPT-11 were used as substrates\nand cultured with liver microsomes in vitro. Imidapril hydrolase activities of recombinant CES1A1 and human liver\nmicrosomes (HLM) were strongly inhibited by sodium lauryl sulphate (SLS) and polyoxyl 40 hydrogenated castor oil (RH40)\n[Inhibition constant (Ki) = 0.0460.01 mg/ml and 0.2060.09 mg/ml for CES1A1, and 0.1260.03 mg/ml and 0.7660.33 mg/ml,\nrespectively, for HLM]. The enzyme hydrolase activity of recombinant CES2 was substantially inhibited by Tween 20 and\npolyoxyl 35 castor oil (EL35) (Ki = 0.9360.36 mg/ml and 4.461.24 mg/ml, respectively). Thus, these results demonstrate that\nsurfactants such as SLS, RH40, Tween 20 and EL35 may attenuate the CES activity; such inhibition should be taken into\nconsideration during drug administration.
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