title: 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 (t1/2=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 (t1/2=21+/-3s) 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 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.
authors.affiliation: Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FI-70211 Kuopio, Finland. Hanna.Kumpulainen@uku.fi
authors.forename: Hanna
authors.initials: H
authors.lastname: Kumpulainen
authors.forename: Tomi
authors.initials: T
authors.lastname: Järvinen
authors.forename: Anne
authors.initials: A
authors.lastname: Mannila
authors.forename: Jukka
authors.initials: J
authors.lastname: Leppänen
authors.forename: Tapio
authors.initials: T
authors.lastname: Nevalainen
authors.forename: Antti
authors.initials: A
authors.lastname: Mäntylä
authors.forename: Jouko
authors.initials: J
authors.lastname: Vepsäläinen
authors.forename: Jarkko
authors.initials: J
authors.lastname: Rautio
mesh_terms: D000469:Alkaline Phosphatase / Q000737:chemistry; D018686:Anesthetics, Intravenous / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D002021:Buffers; D002851:Chromatography, High Pressure Liquid; D002855:Chromatography, Thin Layer; D006868:Hydrolysis; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D010710:Phosphates / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D015742:Propofol / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility; D012996:Solutions; D013056:Spectrophotometry, Ultraviolet
chemical_list: D018686:Anesthetics, Intravenous; D002021:Buffers; D007202:Indicators and Reagents; D010710:Phosphates; D011355:Prodrugs; D012996:Solutions; D000469:Alkaline Phosphatase; D015742:Propofol