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In vitro evaluation of the inhibitory potential of pharmaceutical excipients on human carboxylesterase 1A and 2.

Zhang C, Xu Y, Zhong Q, Li X, Gao P, Feng C, Chu Q, Chen Y, Liu D - PLoS ONE (2014)

Bottom Line: In this study, the inhibitory effects of 25 excipients on the activities of CES1A1 and CES2 were evaluated.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Tongji hospital, Tongji medical school, Huazhong University of Science and Technology, Wuhan, Hubei, China.

ABSTRACT
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.

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Inhibitory effects of excipients on CES1A1 and CES2.Inhibitory effects of 25 excipients on imidapril hydrolase activity of recombinant CES1A1 (A) and on CPT-11 hydrolase activity of recombinant CES2 (B). The concentrations of imidapril and CPT-11 were 100 μM and 5 μM, and the concentrations of the tested excipients were 500 μM except that F68, EL35, RH40, lecithin, PVP and Sodium alginate were 100 μg/ml. Each column represents the mean ± SD. The control activity was 1.83 nmol/min/mg and 13.7 pmol/min/mg for CES1A1 and CES2, respectively.
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pone-0093819-g001: Inhibitory effects of excipients on CES1A1 and CES2.Inhibitory effects of 25 excipients on imidapril hydrolase activity of recombinant CES1A1 (A) and on CPT-11 hydrolase activity of recombinant CES2 (B). The concentrations of imidapril and CPT-11 were 100 μM and 5 μM, and the concentrations of the tested excipients were 500 μM except that F68, EL35, RH40, lecithin, PVP and Sodium alginate were 100 μg/ml. Each column represents the mean ± SD. The control activity was 1.83 nmol/min/mg and 13.7 pmol/min/mg for CES1A1 and CES2, respectively.

Mentions: The inhibitory effects of the 25 excipients on the imidapril hydrolase activity of human recombinant CES1A1 were investigated (Fig.1A). DMSO (0.1%) inhibited the imidapril hydrolase activity of CES1A1 by 0.92%. The inhibition rates of the excipients dissolved in DMSO were calculated as the percentages of the tested activity compared with that of the control one after eliminating the impact of 0.1% DMSO. Imidaprilat formation catalyzed by CES1A1 was strongly inhibited by SLS (percentage of control: 2.9%), RH40 (6.7%), S40 (15%), EL35 (12.5%) and Tween 20 (14.4%). The activity of recombinant CES1A1 was moderately inhibited by PEG 400 and Tween 80 (20%–50% of the control), whereas all the remaining excipients inhibited less than 50% of the imidapril hydrolase activity.


In vitro evaluation of the inhibitory potential of pharmaceutical excipients on human carboxylesterase 1A and 2.

Zhang C, Xu Y, Zhong Q, Li X, Gao P, Feng C, Chu Q, Chen Y, Liu D - PLoS ONE (2014)

Inhibitory effects of excipients on CES1A1 and CES2.Inhibitory effects of 25 excipients on imidapril hydrolase activity of recombinant CES1A1 (A) and on CPT-11 hydrolase activity of recombinant CES2 (B). The concentrations of imidapril and CPT-11 were 100 μM and 5 μM, and the concentrations of the tested excipients were 500 μM except that F68, EL35, RH40, lecithin, PVP and Sodium alginate were 100 μg/ml. Each column represents the mean ± SD. The control activity was 1.83 nmol/min/mg and 13.7 pmol/min/mg for CES1A1 and CES2, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3974814&req=5

pone-0093819-g001: Inhibitory effects of excipients on CES1A1 and CES2.Inhibitory effects of 25 excipients on imidapril hydrolase activity of recombinant CES1A1 (A) and on CPT-11 hydrolase activity of recombinant CES2 (B). The concentrations of imidapril and CPT-11 were 100 μM and 5 μM, and the concentrations of the tested excipients were 500 μM except that F68, EL35, RH40, lecithin, PVP and Sodium alginate were 100 μg/ml. Each column represents the mean ± SD. The control activity was 1.83 nmol/min/mg and 13.7 pmol/min/mg for CES1A1 and CES2, respectively.
Mentions: The inhibitory effects of the 25 excipients on the imidapril hydrolase activity of human recombinant CES1A1 were investigated (Fig.1A). DMSO (0.1%) inhibited the imidapril hydrolase activity of CES1A1 by 0.92%. The inhibition rates of the excipients dissolved in DMSO were calculated as the percentages of the tested activity compared with that of the control one after eliminating the impact of 0.1% DMSO. Imidaprilat formation catalyzed by CES1A1 was strongly inhibited by SLS (percentage of control: 2.9%), RH40 (6.7%), S40 (15%), EL35 (12.5%) and Tween 20 (14.4%). The activity of recombinant CES1A1 was moderately inhibited by PEG 400 and Tween 80 (20%–50% of the control), whereas all the remaining excipients inhibited less than 50% of the imidapril hydrolase activity.

Bottom Line: In this study, the inhibitory effects of 25 excipients on the activities of CES1A1 and CES2 were evaluated.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacy, Tongji hospital, Tongji medical school, Huazhong University of Science and Technology, Wuhan, Hubei, China.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus