不同物种皮肤酯酶活性的比较。
Comparison of skin esterase activities from different species.
作者信息
Prusakiewicz Jeffery J, Ackermann Chrisita, Voorman Richard
机构信息
Department of Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, 2800 Plymouth Rd., Ann Arbor, Michigan 48105, USA.
出版信息
Pharm Res. 2006 Jul;23(7):1517-24. doi: 10.1007/s11095-006-0273-y. Epub 2006 Jun 21.
PURPOSE
Many topically applied drugs contain esters that are hydrolyzed in the skin. Minipigs have emerged as potential models of human dermatology and, in some aspects, may be superior to commonly used rat skin. The aims of this study were to evaluate the suitability of minipig and rat skin as in vitro models of human epidermal esterase activity.
METHODS
Naphthyl acetate and para-nitrophenyl acetate were tested as prototypical substrates of carboxylesterases from skin, plasma, and liver. Reaction products were monitored by high-performance liquid chromatography/ultraviolet analysis.
RESULTS
Hydrolysis efficiency in skin was higher than plasma, but lower than liver. The esterase efficiency of rat skin microsomes (580-1100 min(-1) mg(-1)) was two to three orders of magnitude higher than human (1.3-4.2 min(-1) mg(-1)) and minipig microsomes (1.2-4.2 min(-1) mg(-1)). Rat skin cytosol (80-100 min(-1) mg(-1)) was 2- to 10-fold more efficient than human (2.4-67 min(-1) mg(-1)) or minipig cytosol (18-61 min(-1) mg(-1)). Most importantly, human skin fractions displayed kinetics of hydrolysis very similar to minipig skin.
CONCLUSIONS
These studies show minipig skin as an appropriate, potentially valuable model for human epidermal ester metabolism and support the use of minipig skin in preclinical development of topically applied compounds.
目的
许多局部应用的药物含有在皮肤中水解的酯类。小型猪已成为人类皮肤病学的潜在模型，并且在某些方面可能优于常用的大鼠皮肤。本研究的目的是评估小型猪和大鼠皮肤作为人类表皮酯酶活性体外模型的适用性。
方法
以醋酸萘酯和对硝基苯乙酸酯作为皮肤、血浆和肝脏中羧酸酯酶的典型底物进行测试。通过高效液相色谱/紫外分析监测反应产物。
结果
皮肤中的水解效率高于血浆，但低于肝脏。大鼠皮肤微粒体的酯酶效率（580 - 1100 min⁻¹ mg⁻¹）比人类（1.3 - 4.2 min⁻¹ mg⁻¹）和小型猪微粒体（1.2 - 4.2 min⁻¹ mg⁻¹）高两到三个数量级。大鼠皮肤胞质溶胶（80 - 100 min⁻¹ mg⁻¹）的效率比人类（2.4 - 67 min⁻¹ mg⁻¹）或小型猪胞质溶胶（18 - 61 min⁻¹ mg⁻¹）高2至10倍。最重要的是，人类皮肤组分显示出与小型猪皮肤非常相似的水解动力学。
结论
这些研究表明小型猪皮肤是人类表皮酯代谢的合适且可能有价值的模型，并支持在局部应用化合物的临床前开发中使用小型猪皮肤。
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