Synthesis, in vitro and in vivo characterization of novel ethyl dioxy phosphate prodrug of propofol

Abstract

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. The results show that 3 greatly enhanced the aqueous solubility of propofol (solubility over 10 mg/mL) and the stability in buffer solution ( t 1/2 = 5.2 ± 0.2 days at pH 7.4, r.t.) was sufficient for i.v. administration. The enzymatic hydrolysis of 3 to propofol was extremely rapid in vitro ( t 1/2 = 21 ± 3 s) and 3 was readily converted to propofol in vivo in rats. 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 μg/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.