环孢素A前药在人泪液与兔泪液中的转化。

Conversion of cyclosporine A prodrugs in human tears vs rabbits tears.

作者信息

Lallemand F, Felt-Baeyens O, Rudaz S, Hamel A R, Hubler F, Wenger R, Mutter M, Besseghir K, Gurny R

机构信息

Laboratory of Pharmaceutical Technology and Biopharmaceutics, School of Pharmacy, University of Geneva, Geneva, Switzerland.

出版信息

Eur J Pharm Biopharm. 2005 Jan;59(1):51-6. doi: 10.1016/j.ejpb.2004.07.002.

DOI:10.1016/j.ejpb.2004.07.002

PMID:15567301

Abstract

The aim of this study was to evaluate the rate and mechanism of conversion of two water-soluble prodrugs of cyclosporine A (CsA) intended for topical delivery to the eye. The new molecules were designed according to the double prodrug concept: a solubilizing moiety was grafted onto CsA via an ester function, which could be hydrolysed via a two-step process (enzymatic and chemical). Prodrug solutions were prepared extemporaneously in an isotonic and neutral aqueous medium compatible with ophthalmic use. The rates of conversion into the parent molecule were determined by incubating the prodrugs in fresh rabbit or human tears or in a phosphate buffer solution (PBS) at pH 7.4. Both prodrugs were converted into CsA within the first minute in the presence of rabbit tears with rate constants of k=5.9x10(-3)min(-1) and k=3.8x10(-3)min(-1), respectively, for UNIL088 and UNIL089, whereas chemical conversion in PBS was negligible (k=0.5x10(-3)min(-1) for both molecules). Incubation of UNIL088 in human tears showed a significantly high conversion rate. It is concluded that the developed double prodrugs underwent a bioconversion in physiological media and thus represent promising candidates for topical delivery of CsA to the eye.

摘要

本研究的目的是评估两种用于眼部局部给药的环孢素A（CsA）水溶性前药的转化速率和机制。新分子是根据双前药概念设计的：一个增溶部分通过酯官能团连接到CsA上，该酯官能团可通过两步过程（酶促和化学）水解。前药溶液在与眼科用途兼容的等渗中性水性介质中临时制备。通过将前药在新鲜兔泪或人泪或pH 7.4的磷酸盐缓冲溶液（PBS）中孵育来确定转化为母体分子的速率。在兔泪存在下，两种前药在第一分钟内均转化为CsA，UNIL088和UNIL089的速率常数分别为k = 5.9x10（-3）min（-1）和k = 3.8x10（-3）min（-1），而在PBS中的化学转化可忽略不计（两种分子的k = 0.5x10（-3）min（-1））。UNIL088在人泪中的孵育显示出显著高的转化率。结论是，所开发的双前药在生理介质中经历了生物转化，因此是CsA眼部局部给药的有前途的候选物。