Diffusion of n-butyl-p-aminobenzoate (BAB) , lidocaine and bupivacaine through the human dura-arachnoid mater in vitro
Grouls, R.; Korsten, E.; Ackerman, E.; Hellebrekers, L.; van Zundert, A.; Breimer, D.
European Journal of Pharmaceutical Sciences Official Journal of the European Federation for Pharmaceutical Sciences 12(2): 125-131
ISSN/ISBN: 0928-0987 PMID: 11102740 DOI: 10.1016/s0928-0987(00)00147-0
Introduction: Epidural administration of a suspension of n-butyl-p-aminobenzoate (BAB) to humans resulted in a selective, ultra-long lasting sensory block without motor function impairment. The absence of motor block was attributed to 'spatial' confinement of active concentrations of dissolved BAB within the epidural space. This study was designed to investigate the diffusion of BAB through the human dura-arachnoid membrane in vitro relative to lidocaine and bupivacaine and to quantify the influence of the composition of the suspension formulation on this flux. Materials and methods: Human dura-arachnoid specimens were mounted between the donor and the receiver compartment of a diffusion cell. Five concentrations of BAB, lidocaine and bupivacaine in phosphate-buffered saline, pH 7.4, were added to the donor compartment and the increase of the concentration of the agent in time in the receiver compartment was measured by automated UV-spectrometry. Fluxes and permeabilities were calculated. The influence of pH, polysorbate 80 (PS 80) and polyethylene glycol 3350 (PEG 3350) on the flux of BAB in solution and in suspension formulations were analyzed. Results: The flux of both lidocaine and bupivacaine at pH 4 was considerably smaller than at pH 7.4. Permeabilities decreased in the order bupivacaine> lidocaine mchgt BAB and at the level T12>T1. PS 80 at concentrations exceeding 0.025 mg/ml and PEG 3350 decreased the flux of BAB from BAB-solutions. Used in the preparation of the suspension, PS 80 and PEG 3350 did significantly reduce the permeability. Discussion: The results of this study are consistent with the hypothesis that the selective action of epidurally applied BAB suspension can be attributed to the spatial confinement of active BAB-concentrations within the epidural space. Additives used in the preparation of the aqueous suspension formulation may substantially influence the local pharmacokinetics and by that the pharmacodynamic effects.