The preclinical pharmacological study on HX0969W, a novel water-soluble pro-drug of propofol, in rats

BACKGROUND: Propofol is the most widely used intravenous sedative-hypnotic anesthetic in clinical practice. However, many serious side effects have been related to its lipid emulsion formulation. The pro-drug design approach was used to develop the water-soluble propofol, which could effectively resolve the limitations associated with the lipid emulsion formulation. Thus, the new water-soluble pro-drug of propofol, HX0969W, was designed and synthesized. The objective of this study was to conduct preclinical pharmacological studies on this novel water-soluble pro-drug of propofol. METHODS: The assessment of the loss of the righting reflex (LoRR) was used for the pharmacodynamic study, and liquid chromatography-tandem mass spectrometry and high-performance liquid chromatography- fluorescence were used for the pharmacokinetic study. RESULTS: The potency of HX0969W (ED(50) [95% CI], 46.49 [43.89–49.29] mg/kg) was similar to that of fospropofol disodium (43.66 [43.57–43.75] mg/kg), but was lower than that of propofol (4.82 [4.8–14.82] mg/kg). Administered with a dose of 2-fold ED(50), propofol required a shorter time to cause LoRR than that of HX0969W and fospropofol. However, the LoRR duration was significantly longer in response to the administration of HX0969W and fospropofol disodium than that caused by propofol. In the pharmacokinetic study, the C(max) of fospropofol was higher than that of HX0969W. HX0969W had a shorter mean residual time and a rapid clearance rate than that of fospropofol disodium. There was no significant difference between the T(max) of the propofol whether it was released by HX0969W or fospropofol disodium; the C(max) of propofol released by HX0969W was similar to that of propofol, which was higher than the propofol released by fospropofol disodium.