Kapoor Mamta, Siegel Ronald A
Departments of Pharmaceutics and ‡Biomedical Engineering, University of Minnesota , Minneapolis, Minnesota 55455, United States.
Mol Pharm. 2013 Sep 3;10(9):3519-24. doi: 10.1021/mp400272m. Epub 2013 Aug 12.
Poor water solubility of APIs is a key challenge in drug discovery and development as it results in low drug bioavailability upon local or systemic administration. The prodrug approach is commonly utilized to enhance solubility of hydrophobic drugs. However, for accelerated drug absorption, supersaturated solutions need to be employed. In this work, a novel prodrug/enzyme based system was developed wherein prodrug and enzyme are coadministered at the point of absorption (e.g., nasal cavity) to form in situ supersaturated drug solutions for enhanced bioavailability. A combination of fosphenytoin/alkaline phosphatase was used as a model system. Prodrug conversion kinetics were evaluated with various prodrug/enzyme ratios at pH 7.4 and 32 °C. Phenytoin permeation rates were determined at various degrees of supersaturation (S = 0.8-6.1), across confluent Madin Darby canine kidney II-wild type monolayers (a nasal epithelium model), with prodrug and enzyme spiked into the apical chamber. Membrane intactness was confirmed by measuring transepithelial electrical resistance and inulin permeability. Fosphenytoin and phenytoin concentrations were analyzed using HPLC. Results indicated that a supersaturated solution could be formed using such prodrug/enzyme systems. Drug absorption increased proportionately with increasing degrees of supersaturation; this flux was 1.5-6 fold greater than that for the saturated phenytoin solution. The experimental data fitted reasonably well to a two compartment pharmacokinetic (PK) model with first order conversion of prodrug to drug. This prodrug/enzyme system markedly enhances drug transport across the model membrane. Applied in vivo, this strategy could be used to facilitate drug absorption through mucosal membranes when absorption is limited by solubility.
活性药物成分（APIs）的低水溶性是药物研发中的一个关键挑战，因为这会导致局部或全身给药后药物生物利用度较低。前药方法通常用于提高疏水性药物的溶解度。然而，为了加速药物吸收，需要使用过饱和溶液。在这项工作中，开发了一种新型的基于前药/酶的系统，其中前药和酶在吸收部位（如鼻腔）共同给药，以形成原位过饱和药物溶液，从而提高生物利用度。磷苯妥英/碱性磷酸酶的组合被用作模型系统。在pH 7.4和32°C下，用不同的前药/酶比例评估前药转化动力学。在不同的过饱和度（S = 0.8 - 6.1）下，将前药和酶加入到顶端腔室中，测定苯妥英在汇合的Madin Darby犬肾II型野生型单层细胞（一种鼻上皮模型）上的渗透速率。通过测量跨上皮电阻和菊粉通透性来确认膜的完整性。使用高效液相色谱法分析磷苯妥英和苯妥英的浓度。结果表明，使用这种前药/酶系统可以形成过饱和溶液。药物吸收随着过饱和度的增加成比例增加；该通量比饱和苯妥英溶液的通量高1.5 - 6倍。实验数据与前药一级转化为药物的二室药代动力学（PK）模型拟合良好。这种前药/酶系统显著增强了药物在模型膜上的转运。在体内应用时，当吸收受溶解度限制时，该策略可用于促进药物通过粘膜的吸收。
