Kumpulainen Hanna, Järvinen Tomi, Mannila Anne, Leppänen Jukka, Nevalainen Tapio, Mäntylä Antti, Vepsäläinen Jouko, Rautio Jarkko
Department of Pharmaceutical Chemistry, University of Kuopio, PO Box 1627, FI-70211 Kuopio, Finland.
Eur J Pharm Sci. 2008 Jul 3;34(2-3):110-7. doi: 10.1016/j.ejps.2008.02.121. Epub 2008 Mar 2.
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.
合成了一种新型的丙泊酚乙基二氧基磷酸酯前药（3），并在体外和体内对其进行了表征，它是膦酰氧基甲基前药更安全的替代物。3的合成通过乙烯基和1-氯乙基醚中间体实现，随后添加磷酸基团。在缓冲溶液中测定了3的水溶性和化学稳定性，并在体外和体内测定了3向丙泊酚的生物转化。结果表明，3大大提高了丙泊酚的水溶性（溶解度超过10mg/mL），并且在缓冲溶液中的稳定性（在pH7.4、室温下t1/2=5.2±0.2天）足以用于静脉给药。3在体外酶促水解为丙泊酚的速度极快（t1/2=21±3秒），并且3在大鼠体内很容易转化为丙泊酚。在生物转化过程中，3释放出乙醛，乙醛的毒性低于丙泊酚膦酰氧基甲基前药（Aquavan，正在进行临床试验）释放的甲醛。静脉注射3后，在2.1±0.8分钟内达到丙泊酚的最大血浆浓度，为3.0±0.2μg/mL。本研究表明，乙基二氧基磷酸酯代表了一种潜在有用的适合静脉给药的水溶性前药结构。
