Limits...
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.

Show MeSH

Related in: MedlinePlus

IC50 values of excipients for CES1A1 and CES2.IC50 values of SLS (A), RH40 (B), Tween 20 (C) and EL 35 (D) on the p-nitrophenyl acetate hydrolase activities of recombinant CES1A1 and CES2. Microsomes were incubated with 150 μM p-nitrophenyl acetate in the presence of excipients of various concentrations. Activities were expressed as a percentage of the tested activity compared with the control. Each data point represents the mean ± SD. The control activities by recombinant CES1A1 and CES2 were 3.95 nmol/min/mg and 40.6 pmol/min/mg, respectively.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3974814&req=5

pone-0093819-g005: IC50 values of excipients for CES1A1 and CES2.IC50 values of SLS (A), RH40 (B), Tween 20 (C) and EL 35 (D) on the p-nitrophenyl acetate hydrolase activities of recombinant CES1A1 and CES2. Microsomes were incubated with 150 μM p-nitrophenyl acetate in the presence of excipients of various concentrations. Activities were expressed as a percentage of the tested activity compared with the control. Each data point represents the mean ± SD. The control activities by recombinant CES1A1 and CES2 were 3.95 nmol/min/mg and 40.6 pmol/min/mg, respectively.

Mentions: SLS and RH40 intensely inhibited the p-nitrophenyl acetate hydrolase activity of recombinant CES1A1 (Fig. 4A), whereas Tween 20 and EL35 apparently inhibited the activity of recombinant CES2 (Fig. 4B). To further compare the inhibitory effects of SLS, RH40, Tween 20 and EL35 on CES1A1 and CES2 enzyme activities, the IC50 values of p-nitrophenyl acetate hydrolase activity were determined (Fig. 5) using 150 μM substrate. The IC50 values of SLS and RH40 for recombinant CES1A1 were 0.20 μg/ml and 1.48 μg/ml, respectively, while those of Tween 20 and EL35 were 7.94 μg/ml and 12.59 μg/ml, respectively. On the other hand, the IC50 values of Tween 20 and EL35 for recombinant CES2 were 3.16 μg/ml and 8.22 μg/ml, respectively, and those of SLS and RH40 were 0.30 μg/ml and 4.05 μg/ml, respectively. Thus, the excipients demonstrated varied inhibitory effects on the activities of CES1A1 and CES2.


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)

IC50 values of excipients for CES1A1 and CES2.IC50 values of SLS (A), RH40 (B), Tween 20 (C) and EL 35 (D) on the p-nitrophenyl acetate hydrolase activities of recombinant CES1A1 and CES2. Microsomes were incubated with 150 μM p-nitrophenyl acetate in the presence of excipients of various concentrations. Activities were expressed as a percentage of the tested activity compared with the control. Each data point represents the mean ± SD. The control activities by recombinant CES1A1 and CES2 were 3.95 nmol/min/mg and 40.6 pmol/min/mg, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0093819-g005: IC50 values of excipients for CES1A1 and CES2.IC50 values of SLS (A), RH40 (B), Tween 20 (C) and EL 35 (D) on the p-nitrophenyl acetate hydrolase activities of recombinant CES1A1 and CES2. Microsomes were incubated with 150 μM p-nitrophenyl acetate in the presence of excipients of various concentrations. Activities were expressed as a percentage of the tested activity compared with the control. Each data point represents the mean ± SD. The control activities by recombinant CES1A1 and CES2 were 3.95 nmol/min/mg and 40.6 pmol/min/mg, respectively.
Mentions: SLS and RH40 intensely inhibited the p-nitrophenyl acetate hydrolase activity of recombinant CES1A1 (Fig. 4A), whereas Tween 20 and EL35 apparently inhibited the activity of recombinant CES2 (Fig. 4B). To further compare the inhibitory effects of SLS, RH40, Tween 20 and EL35 on CES1A1 and CES2 enzyme activities, the IC50 values of p-nitrophenyl acetate hydrolase activity were determined (Fig. 5) using 150 μM substrate. The IC50 values of SLS and RH40 for recombinant CES1A1 were 0.20 μg/ml and 1.48 μg/ml, respectively, while those of Tween 20 and EL35 were 7.94 μg/ml and 12.59 μg/ml, respectively. On the other hand, the IC50 values of Tween 20 and EL35 for recombinant CES2 were 3.16 μg/ml and 8.22 μg/ml, respectively, and those of SLS and RH40 were 0.30 μg/ml and 4.05 μg/ml, respectively. Thus, the excipients demonstrated varied inhibitory effects on the activities of CES1A1 and CES2.

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