Acylcarnitine chain length influences carnitine-enhanced drug flux through the spinal meninges in vitro.
BACKGROUND
Palmitoyl carnitine has been shown to improve the penetration of hydrophilic drugs through the spinal meninges. Naturally occurring acylcarnitines, however, exist as a homologous series of different acyl chain lengths. The purpose of this study was to determine the most effective acylcarnitine chain length to increase meningeal permeability.


METHODS
The transmeningeal flux of mannitol, morphine, and sufentanil through monkey spinal meninges was determined before and after adding acylcarnitines with chain lengths of 6 to 18 carbon atoms. Flux was measured using a previously established in vitro diffusion cell model.


RESULTS
For mannitol, acylcarnitines generally showed a greater penetration-enhancing effect with increasing chain length, with palmitoyl carnitine (16 carbons) being the most effective compound with an increase of 244 +/- 29% (means +/- SE). Morphine flux was increased most significantly by lauroyl-(12 carbons) and myristoyl-carnitine (14 carbons) with 165 +/- 25% and 188 +/- 44% flux increases, respectively. In contrast, none of the studied acylcarnitines significantly altered the meningeal penetration of the more hydrophobic drug sufentanil.


CONCLUSIONS
The results suggest that, to promote hydrophilic drug penetration, acylcarnitines must surpass a critical chain length (10 carbon units) but should not exceed 16 carbon units. The activity of the acylcarnitines at the spinal meninges is reduced on either side of this range. The ability of acylcarnitines to increase the transmeningeal flux of morphine in vitro suggests that lauroyl or myristoyl carnitine may increase the spinal bioavailability of morphine after epidural administration.
Ummenhofer
W C
WC
University of Washington, Department of Anesthesiology, Seattle RR00166, USA.
Bernards
C M
CM
D000215:Acylation; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002463:Cell Membrane Permeability / Q000187:drug effects*; D004347:Drug Interactions; D066298:In Vitro Techniques; D008254:Macaca nemestrina; D008353:Mannitol / Q000493:pharmacokinetics*; D008578:Meninges / Q000187:drug effects / Q000378:metabolism*; D009020:Morphine / Q000493:pharmacokinetics*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D017409:Sufentanil / Q000493:pharmacokinetics*
D008353:Mannitol; D009020:Morphine; D017409:Sufentanil; D002331:Carnitine