Morris Andrew P, Brain Keith R, Heard Charles M
Welsh School of Pharmacy, Cardiff University, Cardiff CF10 3NB, UK.
Int J Pharm. 2009 Feb 9;367(1-2):44-50. doi: 10.1016/j.ijpharm.2008.09.013. Epub 2008 Sep 18.
Ethyl (HE), propyl (HP), butyl (HB), octyl (HO) and decyl (HD) O-acyl esters of haloperidol (HA) were evaluated for permeation across full-thickness human and guinea pig skin. The inclusion of 0.5mgmL(-1) cetrimide as a receptor phase solubilising agent did not significantly alter the barrier properties of the membranes. The permeation of the parent drug, HA, across guinea pig skin was found to be greater than that of its derivatives. Prodrug hydrolysis by cutaneous esterases was minimal. The permeation of HE, HP and HB across freshly excised guinea pig skin was subsequently investigated, however, prodrug hydrolysis remained low. Hydrolysis studies using a skin extract revealed only limited prodrug metabolism. However, in the presence of a liver extract, hydrolysis of all prodrugs was rapid. It was proposed that GGGX esterases, required for the hydrolysis of tertiary esters, were not present at a sufficiently high concentration within the skin for substantial prodrug hydrolysis to occur. This does not necessarily detract from the system as post-transdermal delivery liberation of HA in vivo is an equally useful mode for delivering this drug to the systemic circulation.
对氟哌啶醇（HA）的乙基（HE）、丙基（HP）、丁基（HB）、辛基（HO）和癸基（HD）O-酰基酯进行了全层人皮肤和豚鼠皮肤渗透评估。在受体相中加入0.5mgmL(-1)的西曲溴铵作为增溶剂，并未显著改变膜的屏障特性。发现母体药物HA透过豚鼠皮肤的渗透率高于其衍生物。皮肤酯酶对前药的水解作用极小。随后研究了HE、HP和HB在新鲜切除豚鼠皮肤上的渗透情况，然而前药水解率仍然很低。使用皮肤提取物进行的水解研究表明，前药代谢有限。然而，在肝脏提取物存在的情况下，所有前药的水解都很快。有人提出，三级酯水解所需的GGGX酯酶在皮肤中的浓度不够高，不足以发生大量前药水解。这不一定会减损该系统的价值，因为HA在体内经皮递送释放是将该药物输送到体循环的同样有用的方式。
