In vitro evaluation of the inhibitory potential of pharmaceutical excipients on human carboxylesterase 1A and 2.
Two major forms of human carboxylesterase (CES), CES1A and CES2, dominate the pharmacokinetics of most prodrugs such as imidapril and irinotecan (CPT-11). Excipients, largely used as insert vehicles in formulation, have been recently reported to affect drug enzyme activity. The influence of excipients on the activity of CES remains undefined. In this study, the inhibitory effects of 25 excipients on the activities of CES1A1 and CES2 were evaluated. Imidapril and CPT-11 were used as substrates and cultured with liver microsomes in vitro. Imidapril hydrolase activities of recombinant CES1A1 and human liver microsomes (HLM) were strongly inhibited by sodium lauryl sulphate (SLS) and polyoxyl 40 hydrogenated castor oil (RH40) [Inhibition constant (Ki) = 0.04 ± 0.01 μg/ml and 0.20 ± 0.09 μg/ml for CES1A1, and 0.12 ± 0.03 μg/ml and 0.76 ± 0.33 μg/ml, respectively, for HLM]. The enzyme hydrolase activity of recombinant CES2 was substantially inhibited by Tween 20 and polyoxyl 35 castor oil (EL35) (K(i) = 0.93 ± 0.36 μg/ml and 4.4 ± 1.24 μg/ml, respectively). Thus, these results demonstrate that surfactants such as SLS, RH40, Tween 20 and EL35 may attenuate the CES activity; such inhibition should be taken into consideration during drug administration.
Department of Pharmacy, Tongji hospital, Tongji medical school, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Chengliang
C
Zhang
Department of Pharmacy, Tongji hospital, Tongji medical school, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Yanjiao
Y
Xu
Hubei Pharmaceutical Industry Research Institute Co. Ltd., Wuhan, Hubei, China.
Qiaoni
Q
Zhong
Department of Pharmacy, Tongji hospital, Tongji medical school, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Xiping
X
Li
Department of Pharmacy, Wuhan Children's Hospital, Wuhan, Hubei, China.
Ping
P
Gao
Department of Pharmacy, Tongji hospital, Tongji medical school, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Chengyang
C
Feng
Department of Oncology, Tongji hospital, Tongji medical school, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Qian
Q
Chu
Department of Oncology, Tongji hospital, Tongji medical school, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Yuan
Y
Chen
Department of Pharmacy, Tongji hospital, Tongji medical school, Huazhong University of Science and Technology, Wuhan, Hubei, China.
Dong
D
Liu
D043182:Carboxylesterase / Q000378:metabolism*; D002368:Castor Oil / Q000494:pharmacology; D005079:Excipients / Q000494:pharmacology*; D006801:Humans; D048289:Imidazolidines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D011136:Polysorbates / Q000494:pharmacology; D012967:Sodium Dodecyl Sulfate / Q000494:pharmacology; D002265:Carboxylic Ester Hydrolases
D043182:Carboxylesterase; D002368:Castor Oil; D005079:Excipients; D048289:Imidazolidines; D011136:Polysorbates; D012967:Sodium Dodecyl Sulfate; C065166:imidapril; C517204:CES2 protein, human; C474609:CES1 protein, human; D002265:Carboxylic Ester Hydrolases