Gullick Darren R, Ingram Matthew J, Pugh W John, Cox Paul A, Gard Paul, Smart John D, Moss Gary P
School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
J Pharm Pharmacol. 2009 Feb;61(2):159-65. doi: 10.1211/jpp/61.02.0004.
To determine the metabolism of captopril n-carboxyl derivatives and how this may impact on their use as transdermal prodrugs. The pharmacological activity of the ester derivatives was also characterised in order to compare the angiotensin converting enzyme inhibitory potency of the derivatives compared with the parent drug, captopril.
The metabolism rates of the ester derivatives were determined in vitro (using porcine liver esterase and porcine ear skin) and in silico (using molecular modelling to investigate the potential to predict metabolism).
Relatively slow pseudo first-order metabolism of the prodrugs was observed, with the ethyl ester displaying the highest rate of metabolism. A strong relationship was established between in-vitro methods, while in-silico methods support the use of in-vitro methods and highlight the potential of in-silico techniques to predict metabolism. All the prodrugs behaved as angiotensin converting enzyme inhibitors, with the methyl ester displaying optimum inhibition.
In-vitro porcine liver esterase metabolism rates inform in-vitro skin rates well, and in-silico interaction energies relate well to both. Thus, in-silico methods may be developed that include interaction energies to predict metabolism rates.
确定卡托普利N - 羧基衍生物的代谢情况，以及这可能如何影响它们作为透皮前药的应用。还对酯衍生物的药理活性进行了表征，以便比较这些衍生物与母体药物卡托普利的血管紧张素转换酶抑制效力。
在体外（使用猪肝酯酶和猪耳皮肤）和计算机模拟（使用分子建模来研究预测代谢的潜力）中测定酯衍生物的代谢速率。
观察到前药相对缓慢的伪一级代谢，其中乙酯显示出最高的代谢速率。体外方法之间建立了很强的关系，而计算机模拟方法支持体外方法的使用，并突出了计算机模拟技术预测代谢的潜力。所有前药均表现为血管紧张素转换酶抑制剂，其中甲酯显示出最佳抑制效果。
体外猪肝酯酶代谢速率能很好地反映体外皮肤代谢速率，计算机模拟相互作用能与两者都有很好的相关性。因此，可以开发包括相互作用能来预测代谢速率的计算机模拟方法。
