Moss Gary P, Gullick Darren R, Cox Paul A, Alexander Cameron, Ingram Matthew J, Smart John D, Pugh W John
School of Pharmacy, University of Hertfordshire, College Lane, Hatfield, Hertfordshire AL10 9AB, UK.
J Pharm Pharmacol. 2006 Feb;58(2):167-77. doi: 10.1211/jpp.58.2.0003.
Most drugs are designed primarily for oral administration, but the activity and stability profiles desirable for this route often make them unsuitable for transdermal delivery. We were therefore interested in designing analogues of captopril, a model drug with poor percutaneous penetration, for which the sustained steady-state blood plasma level associated with transdermal delivery (and which is unattainable orally) would be particularly beneficial. Quantitative structure-permeability relationships (QSPRs) predicted that ester and thiol prodrug derivatives of captopril would have lower maximal transdermal flux (J(m)) than the parent drug, since the increases in permeability coefficient (k(p)) of prodrugs would be outweighed by the reductions in aqueous solubility. Therefore, the aim of this study was to synthesize a series of prodrugs of captopril and to determine if a QSPR model could be used to design therapeutically viable prodrugs. Molecules with the highest predicted k(p) values were synthesized and characterized, and J(m) measured in Franz diffusion cells from saturated aqueous donor across porcine skin (fresh and frozen). In-vitro metabolism was also measured. Captopril and the prodrugs crossed the skin relatively freely, with J(m) being highest for ethyl to butyl esters. Substantial first-order metabolism of the prodrugs was observed, suggesting that their enhanced percutaneous absorption was complemented by their metabolic performance. The results suggested that QSPR models provided excellent enhancements in drug delivery. This was not seen at higher lipophilicities, suggesting that issues of solubility need to be considered in conjunction with any such use of a QSPR model.
大多数药物主要设计用于口服给药，但这种给药途径所需的活性和稳定性特征往往使其不适用于经皮给药。因此，我们对设计卡托普利的类似物感兴趣，卡托普利是一种经皮渗透性较差的模型药物，对于经皮给药而言，与之相关的持续稳态血浆水平（且口服无法达到）将特别有益。定量构效关系（QSPRs）预测，卡托普利的酯类和硫醇前药衍生物的最大经皮通量（J(m)）将低于母体药物，因为前药的渗透系数（k(p)）增加量将被水溶性降低量所抵消。因此，本研究的目的是合成一系列卡托普利前药，并确定QSPR模型是否可用于设计具有治疗可行性的前药。合成并表征了预测k(p)值最高的分子，并在Franz扩散池中测量了从饱和水供体穿过猪皮（新鲜和冷冻）的J(m)。还测量了体外代谢情况。卡托普利及其前药相对自由地穿过皮肤，其中乙酯至丁酯的J(m)最高。观察到前药有大量的一级代谢，这表明它们增强的经皮吸收与其代谢性能相辅相成。结果表明，QSPR模型在药物递送方面有显著增强。在较高亲脂性时未观察到这种情况，这表明在结合使用QSPR模型时需要考虑溶解性问题。
