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Anesth Analg 2002;95:1285-1292 © 2002 International Anesthesia Research Society -------------------------------------------------------------------------------- ANESTHETIC PHARMACOLOGY Propofol Phosphate, a Water-Soluble Propofol Prodrug: In Vivo Evaluation Mariusz G. Banaszczyk, PhD*, Alison T. Carlo*, Violeta Millan*, Adam Lindsey*, Ronald Moss, MD*, Dennis J. Carlo, PhD*, and Sheldon S. Hendler, MD PhD *The Immune Response Corporation, Carlsbad, California; and Vyrex Corporation, La Jolla, California Address correspondence and reprint requests to Mariusz G. Banaszczyk, PhD, Chemistry Department, The Immune Response Corporation, 5935 Darwin Court, Carlsbad, CA 92008. Address e-mail to mbanaszczyk@imnr.com. After a single IV injection of the water-soluble propofol prodrug propofol phosphate (PP) in mice, rats, rabbits, and pigs, propofol was produced rapidly (1–15 min), inducing dose-dependent sedative effects. In mice, the hypnotic dose (HD50), lethal dose (LD50), and safety index (defined as a ratio: LD50/HD50) were 165.4 mg/kg, 600.6 mg/kg, and 3.6, respectively. Propofol was produced with half-lives of 5.3 ± 0.6 min in rats, 2.1 ± 0.6 min in rabbits, and 4.4 ± 2.4 min in pigs. The maximal concentration was dose and species dependent. The elimination half-life was 24 ± 12 min in rats, 21 ± 16 min in rabbits, and 225 ± 56 min in pigs. Propofol generated from PP produced pharmacological effects similar to those described in the literature. We found a correlation between PP dose and duration of sedation with propofol concentrations larger than 1.0 µg/mL, which produced somnolence and sedation in rats and pigs. Adequate sedation and, at large enough doses, anesthetic-level sedation were produced after the administration of PP. Overall, PP, the water-soluble prodrug of propofol, seems to be a viable development candidate for sedative and anesthetic applications. IMPLICATIONS. Propofol phosphate, a water-soluble prodrug of the widely used IV anesthetic propofol, was developed and evaluated in mice, rats, rabbits, and pigs after IV injection. The results of the study clearly demonstrate the feasibility of the prodrug approach to achieve sedative and anesthetic levels of propofol in laboratory animals; this warrants further evaluation in humans. |
4楼2009-04-04 09:50:49
