Fospropofol, a propofol prodrug, is water soluble, but formaldehyde is an active metabolite. (Image source: Anesthesia & Analgesia)

Fospropofol, a propofol prodrug, is water soluble, but formaldehyde is an active metabolite. (Image source: Anesthesia & Analgesia)

Propofol has many advantages over other intravenous anesthetics, including rapid onset and recovery. However, propofol is not soluble in water. To make propofol available for intravenous drug, it must be supplied as a lipid emulsion, where the propofol is bound to the lipid component of the formulation. The lipid presents its own problems. First, it supports microbial growth. Second, in large doses (e.g., ICU infusions) it is associated with hyperlipidemia. Finally, propofol pain on injection is caused by the small amount of free propofol that is not lipid bound. Efforts to decrease the lipid in the emulsion increase the free fraction of propofol, increasing pain on injection.

 

Fospropofol is a water soluble propofol prodrug. However, it has the unfortunate characteristic that liberation of the propofol moiety also liberates an unwelcome metabolite: formaldehyde. While not as ominous as it may sound (small amounts of formaldehyde are produced by normal cellular metabolism), there has been lingering concerns about providing an exogenous of formaldehyde with fospropofol. The other metabolite of propofol metabolism is phosphate, which is associated with genital and rectal burning. It’s unclear whether replacing pain at the site of propofol injection from the standard propofol emulsion for genital burning associated with fospropofol injection is worthwhile from the patient’s perspective.

Dr. Wen-Sheng Zhang, Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, P.R. China, and colleagues described the synthesis and testing of two new propofol prodrugs that incorporate labile amino acid moieties rather than a phosphate group of fospropofol, and therefore do not produce formaldehyde. Their work is published in the current issue of Anesthesia & Analgesia in the article titled “An Improved Design of Water-Soluble Propofol Prodrugs Characterized by Rapid Onset of Action.”

The authors developed four analogs to fospropofol: two phosphate and two amino acid-based prodrugs. They assessed the analogs’ solubility and stability in saline, hydrolysis to propofol in rat plasma, rhesus monkey plasma, and in rat hepatic microsomes, and the minimal dose necessary to achieve a loss of righting reflex in a rodent model. All analogs were soluble and stable in saline. Hydrolysis in rat plasma was variable both in terms of percent of drug hydrolyzed to propofol and the time required to achieve steady state hydrolysis.  The two prodrugs made with amino acids underwent the fastest hydrolysis (less than one minute), yielding the most conversion of prodrug to propofol. As would be expected, they were the most effective at causing loss of righting reflex. The authors concluded that the amino acid-based compounds may be a better alternative to phosphate-based of propofol prodrugs that have slower onset and genital/rectal burning.

The development of a propofol congener that avoids the drawbacks of propofol and fospropofol is certainly of interest.  The work is innovative.  Whether such drugs can be used for the induction of anesthesia, or could replace generic propofol in the present healthcare market is unclear.