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Correspondence

Bupivacaine pharmacokinetics and motor blockade following epidural administration of the bupivacaine-sulphobutylether 7-β-cyclodextrin complex in sheep

Estebe, J. P.; Ecoffey, C.; Dollo, G.; Le Corre, P.; Chevanne, F.; Le Verge, R.

Author Information
European Journal of Anaesthesiology: April 2002 - Volume 19 - Issue 4 - p 308-310

EDITOR:

Epidural anaesthesia using local anaesthetics is currently increasing for regional anaesthesia during routine surgery as well as for regional control of acute and chronic pain. However, local anaesthetics present a relative short duration of action and have potentially major side-effects (i.e. cardiac and neurological toxicity). Thus, there is a need for an improvement in their therapeutic index. This could be obtained by the development of drug-delivery systems that allow a controlled release of these drugs. Among the various ways of obtaining delivery systems, complex formation with the cyclodextrins (CDs) may provide interesting. Natural β-CDs are cyclic oligosaccharides containing seven α-1,4-linked glucopyranose units able to entrap many drugs in their hydrophobic cavities to form non-covalent inclusion compounds (Fig. 1)[1,2]. We demonstrated in an earlier study in rabbit an intensification and prolongation of epidural block when bupivacaine-β-CD was made into a complex with parenterally safe modified β-CDs as compared with bupivacaine alone [3]; similar results were obtained with sciatic nerve block [4].

Figure 1
Figure 1:
Chemical structure of SBE7-β-CD.

The present correspondence reports the pharmacokinetics as well as a pharmacodynamics evaluation of a bupivacaine complex with sulphobutyl ether cyclodextrin derivatives (SBE7-β-CD) following epidural administration in another species, i.e. sheep. Bupivacaine hydrochloride (B-HCl) was used as control.

Methods

Bupivacaine base (B) was obtained by precipitation from an alkaline saturated solution of B-HCl. Two formulations were compared: B-HCl and a B complex with SBE7-β-CD (B-SBE7-β-CD; CAPTISOL®; CyDex, Kansas City, KS, USA), both as solutions containing B at 2 mg mL−1. The complex between B and SBE7-β-CD was formed by complete dissolution of 20 mg B in 10 mL of an aqueous solution of SBE7-β-CD (30% w/v). The mixture was shaken for 48 h to ensure complete dissolution of B. The complex obtained was well characterized; an in vitro study was performed to confirm the formation of a 1 : 1 soluble complex.

Five non-pregnant Lacaune sheep (age 2.5 ± 1 yr, weight 69.8 ± 11.6 kg) were included in accordance with the rules and guidelines concerning the care and use of laboratory animals. The Local Animal Research Committee approved the study. Single-orifice, 19 gauge epidural catheters were inserted percutaneously into the epidural space via the loss of resistance technique to 0.9% NaCl solution at the lumbosacral junction, and the catheters were secured to the back. The same investigator placed all catheters. For each experiment, a new catheter was used.

The pharmacokinetics and pharmacodynamics of epidural B-HCl and B complex with SBE7-β-CD were compared following a crossover and randomized administration (10 mL over 30 s) of a 20 mg dose of bupivacaine with a 4-day wash out between administrations. For biopharmaceutical purposes, an intravenous (i.v.) infusion (20 mg B-HCl over 30 s) was performed 2 weeks later. Because it had been described previously that plain CDs did not induce any motor block after epidural administration [1], only two sheep received an epidural drug-free solution of SBE7-β-CD at the end of the study.

Motor activity of the animals was evaluated by a blinded investigator who was unaware of the formulation. The motor blockade was defined as the animal's ability to support its own weight on its hind limbs. A modification of Bromage's motor block scale was used: level 0: free movements of the animal using hind limbs without limitation; level 1: limited or asymmetrical movements of hind limbs to support the body and walk; level 2: inability to support its own weight on hind limbs with detectable ability to move the hind limb; and level 3: total paralysis of hind limbs.

Blood samples (5 mL) were drawn from an external jugular vein catheter before injection and then at 1, 2, 4, 6, 8, 10, 15, 20, 30, 45, 60, 90, 120, 180 and 240 min. The measurement of plasma B concentration was performed using high performance liquid chromatography [5]. The limit of detection was 2 ng mL−1; the within- and between-day reproducibilities were 2.1 and 5.6% respectively.

Following B administration, the peak plasma concentration (Cmax) and corresponding time to reach Cmax (Tmax) were derived from raw data. Individual plasma concentration data obtained after i.v. administration were analysed according to an open-system model with first-order elimination from the central compartment. Individual absorption kinetics after epidural administration of B-HCl and B-SBE7-β-CD were evaluated. Time corresponding to 10, 50 and 90% absorbed (T10%, T50%, T90%) were derived from raw data and the mean dissolution time (63.2% drug absorbed) was calculated.

Results

After epidural injection, the intensity and duration of the motor block in five sheep are depicted as the median in Figure 2. There was no difference at the onset of complete motor block. There was a slight but insignificant difference in the duration of complete motor blockade (level 3) between treatment groups. However, there was a significant difference in the recovery time (the time between the end of maximum motor block and the total recovery = duration time of both stages 1 and 2) (163 ± 38 versus 207 ± 23 min for B-HCl and B-SBE7-β-CD, respectively). The trend of prolongation of the clinical effect was confirmed by a significant increase of area under the curve of the intensity of motor block as a function of time (332 ± 83 versus 421 ± 85 for B-HCl and B-SBE7-β-CD, respectively). Epidural administration of drug-free SBE7-β-CD solution did not produce any pharmacodynamic effects or any abnormal behaviour.

Figure 2
Figure 2:
Time-course of the median motor block response to epidural administration of bupivacaine 20 mg in five sheep as B-HCl (○) and B-SBE7-β-CD (•).

The influence of the complex with SBE7-β-CD on the biopharmaceutical behaviour of bupivacaine is shown in Figure 3. There was no significant difference in Cmax between the two formulations after epidural administration. However, Tmax was significantly different (11.2 ± 3.6 versus 46.0 ± 13.1 min for B-HCl and B-SBE7-β-CD, respectively). A significant difference was evidenced with the earliest time parameter derived from raw data (T10% = 9.0 ± 4.9 versus 18.9 ± 8.5 min for B-HCl and B-SBE7-β-CD respectively, P < 0.05).

Figure 3
Figure 3:
Mean (±SD) plasma concentration-time curves of bupivacaine after epidural administration in five sheep of bupivacaine 20 mg as B-HCl (○) and B-SBE7-β-CD (•), and after i.v. administration of bupivacaine 20 mg as B-HCl (▵).

Discussion

From a pharmacodynamic aspect, the difference in the duration of action between the two formulations was less marked than that observed previously in a rabbit model using other cyclodextrin complexes [3]. Such a difference was previously described between rabbit and dog models after epidural administration of viscous lidocaine-hyaluronate; a significant difference being observed only in the rabbit model [3,6]. This was probably due to the presence of more epidural fat in sheep. These data highlight the need to consider carefully the absorption kinetics and the pharmacokinetic characteristics of the animal model.

However, the decrease in absorption rare of bupivacaine from the cyclodextrin formulation seems to allow a trend of prolongation of the effect of bupivacaine after epidural administration in sheep. Despite the small number of animals, the area under the curve of the intensity of motor block as a function of time can evaluate the whole motor effect (onset, duration and complete recovery of motor block) produced by drug administration. The mean time-course of the motor blockade was prolonged after B-SBE7-β-CD compared with B-HCl epidural administration, particularly during the recovery time. The effect could not be attributed to an intrinsic effect of SBE7-β-CD since plain SBE7-β-CD epidural administration did not produce any effect in accordance with previous studies [3,4]. Based on the plasma release profiles, it is suggested that the prolongation of the epidural block might be attributed to the slow release of B from SBE7-β-CD. Particularly, the significant difference in Tmax suggested a decrease in the absorption rate into the systemic circulation. Additional work is necessary to define better the potential of cyclodextrins in this area, i.e. the choice of the most appropriate local anaesthetic-cyclodextrin complex.

J. P. Estebe

C. Ecoffey

Centre Hospitalier Régional et Universitaire de Rennes; Service d'Anesthésie et Réanimation 2; Rennes, France

G. Dollo

P. Le Corre

F. Chevanne

R. Le Verge

Université de Rennes I; Laboratoire de Pharmacie Galénique et Biopharmacie; Rennes, France

References

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4. Dollo G, Thompson DO, Le Corre P, Chevanne F, Le Verge R. Inclusion complexation of amide-typed local anesthetics with β-cyclodextrin and its derivatives. III. Biopharmaceutics of bupivacaine-SBE7-β CD complex following percutaneous sciatic nerve administration in rabbits. Int J Pharm 1998; 164: 11-19.
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6. Doherty MM, Hughes PJ, Charman SA, et al. Biphasic drug absorption from the epidural space of the dog may limit the utility of a slow release medium molecular weight hyaluronic acid-lidocaine ionic complex formulation. Anesth Analg 1996; 83: 1244-1250.
© 2002 European Academy of Anaesthesiology