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The systemic absorption and disposition of levobupivacaine 0.5% after epidural administration in surgical patients: a stable-isotope study

Simon, M. J. G.*; Veering, B. T.*; Stienstra, R.*; van Kleef, J. W.*; Williams, S. G. P.; McGuire, G. M.; Burm, A. G. L.*

European Journal of Anaesthesiology:
Original Article

Background and objective: Absorption and disposition kinetics can be studied with a stable-isotope method. The aim of this study was to validate a stable-isotope method for levobupivacaine and to derive the relevant pharmacokinetics after epidural administration.

Methods: Eight volunteers (18-32 yr) received approximately 23 mg of both levobupivacaine and deuterium-labelled levobupivacaine simultaneously by intravenous infusion. Venous blood samples were taken for 8 h. Fifteen patients (23-85 yr) received 19 mL levobupivacaine 0.5% (including a 3 mL test dose) epidurally and, 25 min later, approximately 25 mg deuterium-labelled levobupivacaine (D3-levobupivacaine) intravenously. Arterial blood samples were collected for 24 h. Plasma concentrations were determined using liquid chromatography-mass spectrometry. Plasma concentration-time data were analysed by compartmental and non-compartmental analysis.

Results: Based on the ratio of the normalized areas under the curve of unlabelled and deuterium-labelled levobupivacaine in volunteers, as determined by both compartmental (mean ratio: 1.02, 90% CI: 1.00-1.04) and non-compartmental analysis (mean ratio: 1.02, 90% CI: 1.00-1.03) the two formulations were considered equivalent. In surgical patients the elimination half-life (mean ± SD: 196 ± 65 min), total body clearance (349 ± 114 mL min−1) and volume of distribution at steady state (56 ± 14L), derived by compartmental analysis, were similar to those obtained by non-compartmental analysis. The absorption was bi-phasic. The fraction absorbed and half-life of the fast absorption process were 0.22 ± 0.06 and 5.2 ± 2.7 min, respectively. The values for the slow absorption process were 0.84 ± 0.14 and 386 ± 91 min, respectively.

Conclusions: D3-levobupivacaine is pharmacokinetically equivalent to unlabelled levobupivacaine and can be used to study the absorption and disposition kinetics after perineural administration of levobupivacaine in a single experiment.

Author Information

*Leiden University Medical Centre, Department of Anaesthesiology, Leiden, The Netherlands; Inveresk Research International Ltd, Tranent, Scotland, UK

Correspondence to: Mischa Simon, Department of Anaesthesiology (P-5), Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The Netherlands. E-mail:; Tel: +31 71 526 2301; Fax: +31 71 524 8230

Accepted for publication August 2003 EJA 1553

© 2004 European Academy of Anaesthesiology