皮肤羧酸酯酶代谢的立体选择性

目的研究人皮肤羧酸酯酶代谢的立体选择性，为利用前体药物方法促进透皮吸收提供分子生物学基础。方法以酮洛芬乙酯为模型药物，利用皮肤匀浆代谢方法考察皮肤羧酸酯酶代谢的立体选择性。以人肝脏L02细胞株中羧酸酯酶的表达为对照，采用RT-PCR方法从mRNA水平研究皮肤组织及其细胞中羧酸酯酶的表达。结果 酮洛芬乙酯在人皮肤匀浆中的代谢产物以R-酮洛芬为主。人羧酸酯酶-2(hCE-2)在皮肤组织及其细胞中都有很强的表达，而人羧酸酯酶-1(hCE-1)在皮肤组织及其细胞中的表达量很小或不表达。结论皮肤表达的hCE-2是透皮吸收常用酯类前体药物的主要水解酶，其对手性酯类前体药物的水解具有立体选择性。

Stereoselectivity of skin carboxylesterase metabolism

Aim To study the stereoselectivity of skin carboxylesterase metabolism and its molecular biological foundation for improving drug percutaneous absorption. Methods Ketoprofen ethyl ester was used as a model drug, and skin homogenate was applied for studying the stereoselectivity of carboxylesterase metabolism. Human liver L02 cell was used as control of carboxylesterase expression, and RT-PCR was used for studying the expression of carboxylesterase. Results The main metabolite of ketoprofen ethyl ester in human skin homogenate was R-ketoprofen. Human carboxylesterase-2 was highly expressed in skin and its cells. However, the expression of human carboxylesterase-1 was very weak or not detectable. Conclusion Human carboxylesterase-2 is the main hydrolytic enzyme of prodrugs in percutaneous absorption, and shows metabolic stereoselectivity to prodrugs with chiral esters.