European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences
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Synthesis, in vitro and in vivo characterization of novel ethyl dioxy phosphate prodrug of propofol.
A novel ethyl dioxy phosphate prodrug of propofol (3) was synthesized and characterized in vitro and in vivo as safer alternative for phosphonooxymethyl prodrugs. The synthesis of 3 was achieved via vinyl and 1-chloroethyl ether intermediates, followed by addition of phosphate group. Aqueous solubility and chemical stability of 3 was determined in buffer solutions and the bioconversion of 3 to propofol was determined in vitro and in vivo. ⋯ During bioconversion, 3 releases acetaldehyde, a less toxic compound than the formaldehyde released from the phosphonooxymethyl prodrug of propofol (Aquavan), currently undergoing clinical trials. The maximum plasma concentration of propofol, 3.0+/-0.2 microg/mL, was reached within 2.1+/-0.8 min after the i.v. administration of 3. The present study indicates that ethyl dioxy phosphate represents a potentially useful water-soluble prodrug structure suitable for i.v. administration.