Ex vivo and in vivo diffusion of ropivacaine through spinal meninges: influence of absorption enhancers.
Following epidural administration, cerebrospinal fluid bioavailability of local anesthetics is low, one major limiting factor being diffusion across the arachnoid mater barrier. The aim of this study was to evaluate the influence of absorption enhancers on the meningeal permeability of epidurally administered ropivacaine. Five enhancers known for their ability to increase drug permeability via transcellular and/or paracellular pathways, i.e. palmitoyl carnitine, ethylenediaminetetraacetic acid, sodium caprate, dodecylphosphocholine and pentylglycerol, were tested ex vivo on fresh specimen of meninges removed from cervical to lumbar level of rabbit spine following laminectomy and placed in diffusion chambers. Among them, sodium caprate lead to the best permeability improvement for both marker and drug (440% and 112% for mannitol and ropivacaine, respectively) and was therefore selected for in vivo study in a sheep model using microdialysis technique to evaluate epidural and intrathecal ropivacaine concentrations following epidural administration. Resulting dialysate and plasma concentrations were used to calculate pharmacokinetic parameters. Following sodium caprate pre-treatment, ropivacaine intrathecal maximal concentration (Cmax) was 1.6 times higher (78 ± 16 μg ml(-1) vs 129 ± 26 μg ml(-1), p<0.05) but the influence of the absorption enhancer was only effective the first 30 min following ropivacaine injection, as seen with the significantly increase of intrathecal AUC(0-30 min) (1629 ± 437 μg min ml(-1) vs 2477 ± 559 μg min ml(-1), p<0.05) resulting in a bioavailable fraction 130% higher 30 min after ropivavaine administration. Co-administration of local anesthetics with sodium caprate seems to allow a transient and reversible improvement of transmeningeal passage into intrathecal space.
Laboratoire de Pharmacie Galénique, Biopharmacie et Pharmacie Clinique, Faculté de Pharmacie, Université de Rennes 1, 35043 Rennes Cedex, France.
Nolwenn
N
Brandhonneur
Gilles
G
Dollo
Maja
M
Ratajczak-Enselme
Anne Laure
AL
Deniau
François
F
Chevanne
Jean Pierre
JP
Estèbe
Alain
A
Legrand
Pascal
P
Le Corre
D000042:Absorption; D000577:Amides / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000737:chemistry / Q000493:pharmacokinetics*; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000097:blood / Q000134:cerebrospinal fluid / Q000737:chemistry / Q000493:pharmacokinetics*; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D003652:Decanoic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D004058:Diffusion; D004339:Drug Compounding; D004492:Edetic Acid / Q000494:pharmacology; D005990:Glycerol / Q000031:analogs & derivatives / Q000494:pharmacology; D007268:Injections, Epidural; D008578:Meninges / Q000187:drug effects* / Q000378:metabolism; D017551:Microdialysis; D010172:Palmitoylcarnitine / Q000494:pharmacology; D010539:Permeability; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000494:pharmacology; D011817:Rabbits; D000077212:Ropivacaine; D012756:Sheep
D000577:Amides; D000779:Anesthetics, Local; D003652:Decanoic Acids; D010767:Phosphorylcholine; D010172:Palmitoylcarnitine; C031071:decanoic acid; C028810:dodecylphosphocholine; D000077212:Ropivacaine; D004492:Edetic Acid; D005990:Glycerol