sodium-oxybate and fospropofol

Phosphate ester prodrugs of propofol (fospropofol, HX0969W) were designed to avoid the unsatisfactory water solubility of the parent drug. However, in previous clinical trials, there were reported prodrug side effects such as paresthesia and pruritus. The accumulation of a phosphate ester component was found to be the main culprit. To exclude this potential risk, we designed 2 amino acid propofol prodrugs (HX0969-Gly-F3, HX0969-Ala-HCl) based on the lead compound (HX0969) by introducing the amino acid group into the structures of the propofol prodrugs. We hypothesized that the improved propofol prodrugs could not only eliminate those adverse effects but also retain their rapid action and good water solubility.. The lead compound HX0969 was synthesized by the sodium borohydride-iodine system. HX0969W, HX0969-Gly-F3, and HX0969-Ala-HCl were synthesized from HX0969. The solubility of fospropofol, HX0969W, HX0969-Gly-F3, and HX0969-Ala-HCl in normal saline was tested. The bioconversions from those prodrugs to propofol in different physiological media (rat plasma, rhesus monkey plasma, and rat hepatic microsomes) were determined in vitro. An in vivo test in the rats was performed to measure the 50% effective dose (ED50) of the 4 propofol prodrugs. Their action onset time and duration time were also measured after their equipotent doses were given.. (1) The water solubility of fospropofol, HX0969W, HX0969-Gly-F3, and HX0969-Ala-HCl was 461.46 ± 26.40 mg/mL, 189.45 ± 5.02 mg/mL, 49.88 ± 0.58 mg/mL, and 245.99 ± 4.83 mg/mL, respectively; (2) The hydrolysis tests in both the rat plasma and the rhesus monkey plasma revealed that the 2 amino acid prodrugs released propofol to a greater extent at a more rapid rate than the 2 phosphate prodrugs during the testing period of 5 hours. All 4 prodrugs released propofol rapidly in the presence of rat hepatic enzymes; (3) Compared with the previous prodrugs (fospropofol, HX0969W), the 2 novel compounds (HX0969-Gly-F3, HX0969-Ala-HCl) had a much shorter onset time when a much lower dose was given.. Application of the amino acid group to the propofol prodrug can make the prodrug have good water solubility and a more rapid onset of action. In rat plasma, the 2 improved amino acid prodrugs (HX0969-Ala-HCl, HX0969-Gly-F3) had a more rapid rate of propofol release than the 2 phosphate ester prodrugs (fospropofol, HX0969W). The in vivo tests showed that HX0969-Ala-HCl and HX0969-Gly-F3 given IV could have a more rapid onset of action in a smaller dose than fospropofol and HX0969W. This novel design can enhance the efficiency of prodrugs converting to propofol.

Topics: Anesthetics, Intravenous; Animals; Biotransformation; Drug Design; Drug Stability; Formaldehyde; Hydrolysis; In Vitro Techniques; Macaca mulatta; Microsomes, Liver; Organophosphorus Compounds; Phosphates; Prodrugs; Propofol; Rats; Rats, Sprague-Dawley; Sodium Oxybate; Solubility; Water

HX0969w is a novel water-soluble prodrug designed to release propofol and gamma-hydroxybutyrate (GHB) and has a sedative-hypnotic effect. This study was performed to compare the efficacy of HX0969w with fospropofol in mice and rats.. We performed hydrolysis studies in the plasma from mice and rats. The half-maximal effective doses (ED50) and half-maximal lethal doses (LD50) of fospropofol and HX0969w were determined. A pharmacodynamics comparison of these two compounds was also performed. Time to loss of righting reflex, time to return of righting reflex, recovery time, and adverse effects were recorded.. The hydrolysis studies demonstrated that HX0969w released propofol as expected. HX0969w ED50 values in mice and rats were 133.03 and 53.79 mg kg(-1), respectively, and LD50 values were 607.11 and 283.79 mg kg(-1), respectively. The calculated therapeutic index (TI), safety index (SI), and certain safety factor (CSF) of HX0969w were 4.56, 3.33, and 2.92 for mice, and 5.28, 3.94, and 3.49 for rats, respectively. The pharmacodynamic comparison studies suggest that HX0969w has a longer onset time and shorter duration than fospropofol.. Similar to fospropofol, HX0969w is an effective, water-soluble prodrug that is capable of inducing a sedative-hypnotic effect in mice and rats. Unlike fospropofol, HX0969w releases GHB instead of formaldehyde. Further studies regarding the efficacy and safety of HX0969w are necessary.

Topics: Anesthesia, Intravenous; Anesthetics, Intravenous; Animals; Dose-Response Relationship, Drug; Hydrolysis; Lethal Dose 50; Male; Mice; Organophosphorus Compounds; Prodrugs; Propofol; Rats; Rats, Sprague-Dawley; Reflex; Sodium Oxybate; Solubility