Prodrug/Enzyme based acceleration of absorption of hydrophobic drugs: an in vitro study

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.