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

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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 ( IF 4.9 ) Pub Date : 2020-06-30 , DOI: 10.1021/acsptsci.0c00051
Jillian G Baker _{1,

2} , Christophe Fromont ₃ , Marjorie Bruder ₂ , Kevin S J Thompson ₁ , Barrie Kellam _{2,

3} , Stephen J Hill _{1,

2} , Sheila M Gardiner ₁ , Peter M Fischer _{2,

3}

Affiliation

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.

中文翻译：

使用酯酶选择性确定系统可用性的体内持续时间和局部β受体阻滞剂的系统性副作用。

对于皮肤，眼睛，耳朵和呼吸道的疾病，直接递送至目标器官的局部药物是治疗选择。与全身性口服治疗相比，局部治疗的益处包括起效更快，规避肝脏首过药物代谢以及减少全身性副作用。尽管如此，许多局部用药仍会发生一些全身吸收，从而导致全身性副作用。预防这些疾病的一种方法是开发一种药物，该药物在进入血清后会被血清酯酶立即降解。由于局部β受体阻滞剂被用于青光眼和婴儿性血管瘤，并引起全身性副作用，因此使用β肾上腺素受体系统来检验这一假设。纯化的肝酯酶降低了艾司洛尔的表观亲和力，一种用于临床紧急情况的含酯β-受体阻滞剂，其浓度和时间依赖于人类β-肾上腺素能受体。但是，纯化的血清酯酶对艾司洛尔没有影响。合成了新型的含酯β-受体阻滞剂，其中几种对肝和血清酯酶均敏感。尽管好在体外亲和力中，一种这样的化合物2-（3-氯-4-（3-（（2-（3-（3-（3-氯苯基）脲基）乙基）氨基）-2-羟基丙氧基）苯基）乙酸甲酯没有静脉内注射到大鼠中对心率的影响，甚至是等效浓度的艾司洛尔和倍他洛尔剂量的10倍，分别导致心率短暂和持续降低。因此，对血清酯酶敏感的酯基药物为开发真正没有全身副作用的局部用药提供了一种机制。此外，对肝脏和血清酯酶降解的敏感性不同，也可以对其他药物的全身可用性持续时间进行微调。

更新日期：2020-08-14

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