Abstract
BackgroundPropofol 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.MethodsThe 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.ResultsThe potency of HX0969W (ED50 [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 ED50, 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 Cmax 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 Tmax of the propofol whether it was released by HX0969W or fospropofol disodium; the Cmax of propofol released by HX0969W was similar to that of propofol, which was higher than the propofol released by fospropofol disodium.
Highlights
General anesthesia is a combination of drugs, including sedative-hypnotic agents, analgesics, or muscle relaxants, which put the patients in a sleep-like state before surgery or other medical examinations
Due to the pro-drug design, HX0969W and fospropofol disodium are metabolized to propofol, which produces the sedative-hypnotic effect
The Tmax of propofol released by HX0969W or fospropofol disodium in plasma had no significant difference, which was longer than that for propofol (0.5 min)
Summary
General anesthesia is a combination of drugs, including sedative-hypnotic agents, analgesics, or muscle relaxants, which put the patients in a sleep-like state before surgery or other medical examinations. The pro-drug design approach was widely used to develop the novel water-soluble propofol, which could effectively avoid the limitations associated with its lipid emulsion formulation (Feng et al, 2017). A new water-soluble pro-drug of propofol was designed and synthesized in our laboratory (patent number, WO2011160268; denoted as HX0969W), which was metabolized to propofol, γ -hydroxybutyrate (GHB), and phosphate in vivo. In contrast to fospropofol disodium, HX0969W cloud produce an effective sedative-hypnotic effect with lesser potential risks of systemic toxicity. The pro-drug design approach was used to develop the watersoluble propofol, which could effectively resolve the limitations associated with the lipid emulsion formulation. The new water-soluble pro-drug of propofol, HX0969W, was designed and synthesized. There was no significant difference between the Tmax of the propofol whether it was released by HX0969W or fospropofol disodium; the Cmax of propofol released by HX0969W was similar to that of propofol, which was higher than the propofol released by fospropofol disodium
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