Enzyme-mediated precipitation of parent drugs from their phosphate prodrugs

Many oral phosphate prodrugs have failed to improve the rate or extent of absorption compared to their insoluble parent drugs. Rapid parent drug generation via intestinal alkaline phosphatase can result in supersaturated solutions, leading to parent drug precipitation. The purpose was to (1) investigate whether parent drugs can precipitate from prodrug solutions in presence of alkaline phosphatase; (2) determine whether induction times are influenced by (a) dephosphorylation rate, (b) parent drug supersaturation level, and (c) parent drug solubility. Induction times were determined from increases in optical densities after enzyme addition to prodrug solutions of TAT-59, fosphenytoin and estramustine phosphate. Apparent supersaturation ratios (a) were calculated from parent drug solubility at intestinal pH. Precipitation could be generated for all three prodrugs. Induction times decreased with increased enzyme activity and supersaturation level and were within gastrointestinal residence times for TAT-59 concentration greater than or equal to 21 muM (sigma greater than or equal to 210). Induction times for fosphenytoin were less than the GI residence time (199 min) for concentrations of approximately 352 muM (sigma = 4.0). At approximately 475 muM (sigma = 5.3) the induction times were less than 90 min. For estramustine-phosphate, no precipitation was observed within GI residence times. Enzyme-mediated precipitation will depend on apparent supersaturation ratios, parent drug dose, solubility and solubilization by the prodrug. (C) 2003 Elsevier B.V. All rights reserved.