Rozenn Clément

Spray-dryed bupivacaine-loaded microspheres: in vitro evaluation and biopharmaceutics of bupivacaine following brachial plexus administration in sheep

Microspheres could be used as a drug delivery system to prolong the duration of action of bupivacaine and to reduce its systemic absorption leading to high plasma concentrations related to central nervous and cardiovascular toxicity. Bupivacaine-loaded microspheres were made by spray-drying using polylactide-co-glycolide polymers from different sources and with different bupivacaine-polymer ratio. The characterization of microspheres concerned the shape and size, the bupivacaine drug-content (DC) and the cumulative release profiles. We evaluated in sheep the bupivacaine pharmacokinetics: (i) after short intravenous infusion of 75 mg bupivacaine solution; and (ii) following brachial nerve plexus injections of 75 mg bupivacaine solution alone, with the addition of 75 microg epinephrine, with the addition of 150 microg epinephrine and of bupivacaine (750 mg)-loaded microspheres. Release profiles showed a biphasic pattern whatever the DC. After i.v. infusion the mean clearance value was 1.53+/-0.53 l/min and the mean elimination half-life was 120.5+/-73.1 min. Following brachial plexus nerve injection, bupivacaine C(max) were lower than 100 ng/ml following either solution or microspheres administration. Ninety percent of the 75 mg bupivacaine given as a solution were absorbed in 5.8+/-1.0 h (bupivacaine alone) compared to 24.6+/-1.2 h following microsphere administration.

In vitro and in vivo microdialysis calibration using retrodialysis for the study of the cerebrospinal distribution of bupivacaine

Microdialysis coupled to HPLC was used to study the disposition of local anesthetics in the cerebrospinal fluid (CSF) because of the difficulty in sampling CSF. A retrodialysis method for the microdialysis calibration was investigated in vitro and in vivo. Calibration by retrodialysis was simultaneously validated through the use of the zero net flux method. Two local anesthetics (bupivacaine and ropivacaine), which differ structurally by only one methyl group, were respectively utilized as substance of interest and as internal standard. Different parameters were tested in vitro to compare the relative recovery (RR) of bupivacaine and the relative loss (RL) of ropivacaine. Several flow rates were tried to select an optimal in vivo flow rate (1 microliter/min). the RR and RL values were not influenced by the variation of bupivacaine concentration. A significant variability among different probes within a batch was established (RR ranging from 41.1-65.3%; RL ranging from 30.7-61.0%). The K-factor values, defined as RLropivacaine/RLbupivacaine, were calculated in vitro and in vivo. This ratio decreased in vivo but was constant (K in vitro = 1.06 +/- 0.04, K in vivo = 0.87 +/- 0.03). The extracellular tissue concentration of the compound of interest was again in vitro and no deterioration of probe during the in vivo experiment was found. After administration of bupivacaine in the epidural space of rabbits, plasma and microdialysis CSF samples were simultaneously collected. Plasma and CSF disposition of bupivacaine displayed different kinetics. The maximum CSF concentration of B averaged 394 +/- 170 micrograms ml-1 with a mean Tmax of 3.8 +/- 1.8 min. The maximum CSF concentration of B averaged 0.44 +/- 0.09 micrograms ml-1 with a mean Tmax occurring at 1 min. Microdialysis, combined with accurate calibration, should be a reliable technique to gain further insight in the spinal disposition of local anesthetics.

Spinal biopharmaceutics of bupivacaine and lidocaine by microdialysis after their simultaneous administration in rabbits

The aim of the present study was to determine the intrathecal bioavailability of a mixture of lidocaine and bupivacaine in a rabbit model of spinal anesthesia by using the microdialysis technique. Catheter and microdialysis probe were inserted under control of the view either in the epidural or in the intrathecal space. First, the epidural disposition of the mixture of bupivacaine and lidocaine was studied after epidural administration. Then, the intrathecal and plasma dispositions of bupivacaine and lidocaine were investigated following intrathecal or epidural administration. The epidural clearance of bupivacaine was higher than that of lidocaine, suggesting a more significant uptake of bupivacaine into the systemic circulation and/or into the CSF. The intrathecal bioavailability of bupivacaine and lidocaine was 12.3 and 17.9%, respectively, while it was 5.5 and 17.7% following the separate administration of each agent [Clément, R., Malinovsky, J.M., Le Corre, P., Dollo, G., Chevanne, F., Le Verge, R., 1999. Cerebrospinal fluid bioavailability and pharmacokinetics of bupivacaine and lidocaine following intrathecal and epidural administrations in rabbits using microdialysis. J. Pharmacol. Exp. Ther. 289, 1015-21]. After intrathecal administration, a decrease in C(max) and AUC values was observed for bupivacaine in comparison with the separate administration. Moreover, after epidural administration, the systemic resorption was slower and lower, especially for bupivacaine. Such a reduction in the systemic absorption of bupivacaine might increase its intrathecal bioavailability, resulting from a vasoconstrictor effect of lidocaine reducing the systemic absorption of bupivacaine from the epidural space leading to an increase of its extent of absorption through meninges into CSF although its absorption rate was not modified.

Effect of dexamethasone on motor brachial plexus block with bupivacaine and with bupivacaine-loaded microspheres in a sheep model.

Background and objective: It has been suggested that dexamethasone potentiates the sensory block produced by bupivacaine when both drugs are loaded in microspheres. The aim of the study was to evaluate the effect of dexamethasone on the brachial plexus block obtained with plain bupivacaine and bupivacaine-loaded microspheres. Methods: Dexamethasone alone (Group 5) or added to plain bupivacaine (75 mg) with (Groups 3 and 4) and without pH correction (Group 2) was compared with plain bupivacaine (75 mg; Group 1). The effect of a small dose of dexamethasone (0.42 mg) was then evaluated on the brachial plexus block obtained with bupivacaine (750 mg) as bupivacaine-loaded microspheres (Group 6). Dexamethasone was added either in the suspending medium (Group 7) or incorporated with bupivacaine into microspheres (Group 8). The motor block was evaluated in a plexus brachial sheep model. Results: Dexamethasone alone did not produce any motor block. When added to plain bupivacaine without pH correction, complete motor block could not be obtained. When the pH was corrected, addition of dexamethasone to plain bupivacaine seemed to delay the onset of motor block and did not prolong its duration, and it had no effect on the pharmacokinetics of bupivacaine. With bupivacaine-loaded microspheres, the duration of complete motor block was reduced when a small dose of dexamethasone was added in the suspending medium. However, the duration of motor block was significantly prolonged when dexamethasone was incorporated with bupivacaine into microspheres. Conclusions: Despite the delayed onset of motor block, the incorporation of dexamethasone in bupivacaine-loaded microspheres dramatically increases the duration of action (700 ± 485-5160 ± 2136 min), which could be clinically relevant when such a drug-delivery system will be available.

Spinal Disposition and Meningeal Permeability of Local Anesthetics

AbstractPurpose. 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.