Oral phosphate prodrugs: Absorption rate limit considerations.

Objectives. Phosphate ester prodrugs substantially enhance the aqueous solubility of some poorly soluble parent drugs due to ionization of the phosphate group at physiological pH. While phosphate prodrugs have proven successful in parenteral formulations, few oral phosphate prodrugs have been marketed to date as they have generally failed to improve parent drug absorption. The objective of this research was to investigate the absorption rate determinants of phosphate prodrugs, namely, (a) solubility-dissolution, (b) permeability, (c) enzymatic bioconversion by alkaline phosphatase, and (d) parent drug precipitation from prodrug solutions of phosphorylated drugs. Methods. The prodrugs, miproxifene phosphate (TAT-59), entacapone phosphate and fosphenytoin were selected for experimental evaluation of the absorption rate limits. Caco-2 cells, in-situ rat intestinal perfusion, UV-vis spectrometry, HPLC and mass spectrometry were among the experimental techniques employed. Parent drug absorptive flux, permeability and supersaturation level were determined in Caco-2 cell monolayers. In vitro precipitation induction times of parent drugs from prodrug/intestinal alkaline phosphatase solutions were also determined. The role of solubility and dose in the selection of suitable oral prodrug candidates was investigated for more than ten prodrugs. A Prodrug Number (PN), analogous to the dose number, was defined as highest targeted oral parent equivalent Dose/250 mL/Csmin, where Csmin is the lowest solubility at intestinal pH. Results. Prodrugs were dephosphorylated in apical Caco-2 chambers. Absorptive fluxes of DP-TAT-59 and phenytoin increased up to 9.8 and 3.3-fold for TAT-59 and fosphenytoin, respectively, compared to their parent drugs while permeability/bioconversion limited parent drug absorption from entacapone-phosphate. Parent drug precipitation induction times from TAT-59, fosphenytoin, and estramustine phosphate, mediated by alkaline phosphatase, decreased with increased enzyme activity and supersaturation level. Estramustine solubilization in prodrug solutions is postulated to reduce enzyme-mediated precipitation potential. Conclusions. Ideal, functional oral phosphate prodrug candidates like DP-TAT-59 have high permeability, low aqueous solubility, and a high-targeted dose (high PN). Early PN assessment is recommended since no absorption advantage is gained for parent drugs administered at sufficiently low doses to permit complete dissolution during the intestinal residence time. Phosphate prodrugs are not likely to optimize oral absorption of parent drugs with low permeability/high solubility, such as entacapone.PhDHealth and Environmental SciencesPharmaceutical sciencesPharmacy sciencesPure SciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/123400/2/3079459.pd