Gastrointestinal delivery of propofol from fospropofol: its bioavailability and activity in rodents and human volunteers

Journal of Translational Medicine

Barbara S Slusher⁵  Rana Rais⁴  Ying Wu¹  Bipin M Mistry²  James J Vornov³  Krystyna M Wozniak¹ 

[1] Johns Hopkins Drug Discovery, Johns Hopkins School of Medicine, The John G. Rangos, Sr. Building, 855 N. Wolfe Street, Baltimore 21205, MD, USA;Center for Veterinary Medicine, FDA, Derwood, MD, USA;Medpace, Cincinnati, OH, USA;Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA;Department of Psychiatry, and Neuroscience, Johns Hopkins School of Medicine, Baltimore, MD, USA

关键词: Hyperalgesia;    Pain;    Non-IV;    Prodrug;    Propofol;   

Others  :  1212314
DOI  :  10.1186/s12967-015-0526-9

 received in 2015-02-06, accepted in 2015-05-08,  发布年份 2015

【 摘 要 】

Background

Propofol is a safe and widely used intravenous anesthetic agent, for which additional clinical uses including treatment of migraine, nausea, pain and anxiety have been proposed (Vasileiou et al. Eur J Pharmacol 605:1–8, 2009). However, propofol suffers from several disadvantages as a therapeutic outside anesthesia including its limited aqueous solubility and negligible oral bioavailability. The purpose of the studies described here was to evaluate, in both animals and human volunteers, whether fospropofol (a water soluble phosphate ester prodrug of propofol) would provide higher propofol bioavailability through non-intravenous routes.

Methods

Fospropofol was administered via intravenous, oral and intraduodenal routes to rats. Pharmacokinetic and pharmacodynamic parameters were then evaluated. Based on the promising animal data we subsequently conducted an oral and intraduodenal pharmacokinetic/pharmacodynamic study in human volunteers.

Results

In rats, bioavailability of propofol from fospropofol delivered orally was found to be appreciable, in the order of around 20–70%, depending on dose. Availability was especially marked following fospropofol administration via the intraduodenal route, where bioavailability approximated 100%. Fospropofol itself was not appreciably bioavailable when administered by any route except for intravenous. Pharmacologic effect following oral fospropofol was confirmed by observation of sedation and alleviation of thermal hyperalgesia in the rat chronic constrictive injury model of neuropathic pain. The human data also showed systemic availability of propofol from fospropofol administration via oral routes, a hereto novel finding. Assessment of sedation in human volunteers was correlated with pharmacokinetic measurements.

Conclusions

These data suggest potential utility of oral administration of fospropofol for various therapeutic indications previously considered for propofol.

【 授权许可】

   
2015 Wozniak et al

【 图 表 】

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