Jewell Christopher, Ackermann Chrisita, Payne N Ann, Fate Gwendolyn, Voorman Richard, Williams Faith M
Toxicology Unit, School of Clinical and Laboratory Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom.
Drug Metab Dispos. 2007 Nov;35(11):2015-22. doi: 10.1124/dmd.107.015727. Epub 2007 Jul 30.
The capacity of human, minipig, and rat skin and liver subcellular fractions to hydrolyze the anesthetic ester procaine was compared with carboxylesterase substrates 4-methylumbelliferyl-acetate, phenylvalerate, and para-nitrophenylacetate and the arylesterase substrate phenylacetate. Rates of procaine hydrolysis by minipig and human skin microsomal and cytosolic fractions were similar, with rat displaying higher activity. Loperamide inhibited procaine hydrolysis by human skin, suggesting involvement of human carboxylesterase hCE2. The esterase activity and inhibition profiles in the skin were similar for minipig and human, whereas rat had a higher capacity to metabolize esters and a different inhibition profile. Minipig and human liver and skin esterase activity was inhibited principally by paraoxon and bis-nitrophenyl phosphate, classical carboxylesterase inhibitors. Rat skin and liver esterase activity was inhibited additionally by phenylmethylsulfonyl fluoride and the arylesterase inhibitor mercuric chloride, indicating a different esterase profile. These results have highlighted the potential of skin to hydrolyze procaine following topical application, which possibly limits its pharmacological effect. Skin from minipig used as an animal model for assessing transdermal drug preparations had similar capacity to hydrolyze esters to human skin.
将人、小型猪和大鼠皮肤及肝脏亚细胞组分水解麻醉酯普鲁卡因的能力，与羧酸酯酶底物乙酸4-甲基伞形酮酯、苯戊酸酯和对硝基苯乙酸酯以及芳基酯酶底物苯乙酸酯进行了比较。小型猪和人皮肤微粒体及胞质组分对普鲁卡因的水解速率相似，而大鼠表现出更高的活性。洛哌丁胺抑制人皮肤对普鲁卡因的水解，提示人羧酸酯酶hCE2参与其中。小型猪和人皮肤中的酯酶活性及抑制谱相似，而大鼠代谢酯的能力更强且抑制谱不同。小型猪和人肝脏及皮肤酯酶活性主要受对氧磷和双硝基苯磷酸酯抑制，这两种是典型的羧酸酯酶抑制剂。大鼠皮肤和肝脏酯酶活性还受到苯甲基磺酰氟和芳基酯酶抑制剂氯化汞的抑制，表明酯酶谱不同。这些结果突出了局部应用后皮肤水解普鲁卡因的可能性，这可能会限制其药理作用。用作评估透皮药物制剂动物模型的小型猪皮肤，水解酯的能力与人皮肤相似。
