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 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 (HD 50 ), lethal dose (LD 50 ), and safety in- dex (defined as a ratio: LD 50 /HD 50 ) were 165.4 mg/kg, 600.6 mg/kg, and 3.6, respectively. Propofol was pro- duced 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 maxi- mal 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 g/mL, which produced somnolence and sedation in rats and pigs. Adequate sedation and, at large enough doses, anesthetic-level sedation were produced after the ad- ministration of PP. Overall, PP, the water-soluble pro- drug of propofol, seems to be a viable development can- didate for sedative and anesthetic applications. (Anesth Analg 2002;95:1285–92) P ropofol (2,6-diisopropylphenol) is a widely used IV anesthetic with a short duration of hypnotic activity, rapid emergence from anes- thesia, and minimal accumulation on long-term ad- ministration (1). Some of the disadvantages of propofol, including significant bradycardia, hyper- tension, pain on injection, hypertriglyceridemia on prolonged administration, and the potential for pul- monary embolism (1–7), are believed to be due in large part to its oil-in-water emulsion formulation. Some of these disadvantages could be alleviated by an aqueous formulation, and a number of ap- proaches have been reported. These approaches in- clude aqueous formulation of inclusion complexes of propofol and hydroxypropyl--cyclodextrins (8,9), formulation in polysorbate 80 (10) and in Cre- mophor EL micelles (11), water-soluble propofol an- alogs (12,13), and water-soluble propofol prodrugs (14). The water-soluble prodrug approach was suc- cessfully applied in the past to several water- insoluble drugs, including antibiotics, anesthetics, and steroidal antiinflammatory drugs (15), and seemed appropriate for water-insoluble propofol. In the prodrug approach, the parent drug is modified with cleavable groups that increase the water solu- bility of the parent drug. Among the most common and pharmaceutically acceptable groups are phos- phate monoesters and hemisuccinates— groups that can increase water solubility sufficiently without a major effect on toxicity. Our prodrug approach, as illustrated in Figure 1, was to produce propofol phosphate (PP), a well defined water-soluble prodrug of propofol that is enzymatically converted to propofol and nontoxic inorganic phosphate. An earlier propofol prodrug, propofol sodium hemisuccinate, demonstrated protection of neuronal cells from oxidative injury in vitro (16); it was fur- ther evaluated in vitro and in vivo but was found unsuitable for commercial development as a stable aqueous formulation (Banaszczyk M, unpublished data, 2000). PP demonstrated superior stability in aqueous formulation and is enzymatically con- verted to two products propofol and inorganic phosphate in vitro by human placental alkaline phosphatase (Banaszczyk M, unpublished data). It is also cleaved in vivo to produce these two prod- ucts. We describe here the preliminary evaluation of PP as a water-soluble propofol prodrug in mice, rats, rabbits, and pigs. We also relate PP dose to the Accepted for publication July 10, 2002. 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. DOI: 10.1213/01.ANE.0000031120.74200.D4 ©2002 by the International Anesthesia Research Society 0003-2999/02 Anesth Analg 2002;95:1285–92 1285