Vehicles for lipophilic drugs: implications for experimental design, neuroprotection, and drug discovery.
The delivery of some classes of drugs is challenging. Solubility, absorption, distribution, and duration of action may all be altered by combination with vehicle molecules. It has already been discovered that polyethylene glycol - which is used as a stabiliser in peptide drug formulations - has biological activity in its own right, including potential neuroprotective properties. In this article we review the evidence for confounding activity for four distinct compounds that have been used as solvents and/or carrier molecules for the delivery of lipophilic drugs under investigation for potential neuroprotective properties. We discuss the evidence that cyclodextrins, ethanol, dimethyl sulphoxide, and a castor oil derivative - Cremophor™ EL - have all been found to have mild to moderate neuroprotective effects. We argue that this has probably reduced the statistical power and increased the Type II error rates of neuroprotection experiments that have employed these vehicles, and suggest experimental design considerations to help correct the problem. However, we also note that the properties of these compounds may represent an opportunity for drug development, particularly for the newer compounds that have been subject to only limited experimental investigation.
Department of Pharmacology and Toxicology, School of Medical Sciences, University of Otago, P.O. Box 913, Dunedin, New Zealand. john.ashton@otago.ac.nz.
Jack
J
Rivers-Auty
John C
JC
Ashton
D003505:Cyclodextrins / Q000494:pharmacology*; D004121:Dimethyl Sulfoxide / Q000494:pharmacology*; D055808:Drug Discovery; D000431:Ethanol / Q000494:pharmacology*; D005990:Glycerol / Q000031:analogs & derivatives* / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000008:administration & dosage*; D014677:Pharmaceutical Vehicles / Q000494:pharmacology*; D012107:Research Design; D012995:Solubility
D003505:Cyclodextrins; D018696:Neuroprotective Agents; D014677:Pharmaceutical Vehicles; D000431:Ethanol; C000515:cremophor EL; D005990:Glycerol; D004121:Dimethyl Sulfoxide