Spinal disposition and meningeal permeability of local anesthetics.
OBJECTIVE
To investigate the spinal disposition, the cerebrospinal fluid (CSF) bioavailability, and the ex vivo meningeal permeability of six homologous pipecoloxylidide local anesthetics and to search for correlations with lipophilicity.


METHODS
The ex vivo meningeal permeability was studied on fresh specimen of meninges (dura mater and arachnoid mater) removed from lumbar and cervical level of rabbit spine following laminectomy. Spinal disposition and CSF bioavailability were investigated using microdialysis sampling after simultaneous injection of an equimolar dose of the six homologs in the epidural or in the intrathecal spaces. In a first step, intrathecal and epidural microdialysis were performed after epidural administration. In a second step, intrathecal microdialysis was performed after intrathecal administration.


RESULTS
Permeability through cervical and lumbar meninges was linearly correlated, and the cervical permeability was around 60% of the lumbar permeability. Apparent permeability data showed a parabolic relationship with the lipophilicity of the derivatives with a marked decrease in permeability for log P above 3. In vivo experiments have shown that the absorption rate constant linearly decreased with lipophilicity of the derivatives (0.171 to 0.125 min(-1)) whereas the intrathecal bioavailability, which was low, increased with lipophilicity (7.2 to 15.9%).


CONCLUSIONS
The unexpected increase in CSF bioavailability with a decrease in absorption rate through meninges emphasizes the role of specific competitive clearance and distribution processes in the epidural space.
Clément
Rozenn
R
Laboratoire de Pharmacie Galénique et Biopharmacie, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes, 35043 Rennes Cedex, France.
Malinovsky
Jean-Marc
JM
Hildgen
Patrice
P
Dollo
Gilles
G
Estèbe
Jean Pierre
JP
Chevanne
François
F
Le Verge
Roger
R
Le Corre
Pascal
P
D000779:Anesthetics, Local / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D005260:Female; D008578:Meninges / Q000187:drug effects / Q000378:metabolism*; D010539:Permeability / Q000187:drug effects; D011817:Rabbits; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
D000779:Anesthetics, Local