Using Esterase Selectivity to Determine the in Vivo Duration of Systemic Availability and Abolish Systemic Side Effects of Topical β-Blockers

Baker, Jillian G.; Fromont, Christophe; Bruder, Marjorie; Thompson, Kevin S.J.; Kellam, Barrie; Hill, Stephen J.; Gardiner, Sheila M.; Fischer, Peter M.

Abstract

© 2020 American Chemical Society. For disorders of the skin, eyes, ears, and respiratory tract, topical drugs, delivered directly to the target organ, are a therapeutic option. Compared with systemic oral therapy, the benefits of topical treatments include a faster onset of action, circumventing the liver first pass drug metabolism, and reducing systemic side effects. Nevertheless, some systemic absorption still occurs for many topical agents resulting in systemic side effects. One way to prevent these would be to develop drugs that are instantly degraded upon entry into the bloodstream by serum esterases. Because topical β-blockers are used in glaucoma and infantile hemeangioma and cause systemic side effects, the β-adrenoceptor system was used to test this hypothesis. Purified liver esterase reduced the apparent affinity of esmolol, an ester-containing β-blocker used in clinical emergencies, for the human β-adrenoceptors in a concentration and time-dependent manner. However, purified serum esterase had no effect on esmolol. Novel ester-containing β-blockers were synthesized and several were sensitive to both liver and serum esterases. Despite good in vitro affinity, one such compound, methyl 2-(3-chloro-4-(3-((2-(3-(3-chlorophenyl)ureido)ethyl)amino)-2-hydroxypropoxy)phenyl)acetate, had no effect on heart rate when injected intravenously into rats, even at 10 times the equipotent dose of esmolol and betaxolol that caused short and sustained reductions in heart rate, respectively. Thus, ester-based drugs, sensitive to serum esterases, offer a mechanism for developing topical agents that are truly devoid of systemic side effects. Furthermore, differential susceptibility to liver and serum esterases degradation may also allow the duration of systemic availability for other drugs to be fine-tuned.

Citation

Baker, J. G., Fromont, C., Bruder, M., Thompson, K. S., Kellam, B., Hill, S. J., …Fischer, P. M. (2020). Using Esterase Selectivity to Determine the in Vivo Duration of Systemic Availability and Abolish Systemic Side Effects of Topical β-Blockers. ACS Pharmacology & Translational Science, 3(4), 737-748. https://doi.org/10.1021/acsptsci.0c00051

• Journal Article Type: Article
• Acceptance Date: Jul 1, 2020
• Online Publication Date: Jul 23, 2020
• Publication Date: Aug 14, 2020
• Deposit Date: Jul 2, 2020
• Publicly Available Date: Jul 24, 2021
• Journal: ACS Pharmacology and Translational Science
• Electronic ISSN: 2575-9108
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• Volume: 3
• Issue: 4
• Pages: 737-748
• DOI: https://doi.org/10.1021/acsptsci.0c00051
• Public URL: https://nottingham-repository.worktribe.com/output/4745008
• Publisher URL: https://pubs.acs.org/doi/10.1021/acsptsci.0c00051
• Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Pharmacology & Translational Science, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acsptsci.0c00051