title: The systemic absorption and disposition of levobupivacaine 0.5% after epidural administration in surgical patients: a stable-isotope study.
abstract: 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 clearanc (349 +/- 114 mL min(-1)) and volume of distribution at steady state (56 +/- 14 L), derived by compartmental analysis, were similar to those obtained by non-compartmental analysis. The absorption was bi-phasic. The fractio absorbed and half-life of the fast absorption process were 0.22 +/- 0.06 and 5.2 +/- 2.7 min, respectively. Th 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.
authors.affiliation: Leiden University Medical Centre, Department of Anaesthesiology, Leiden, The Netherlands. M.J.G.Simon@lumc.nl
authors.forename: M J G
authors.initials: MJ
authors.lastname: Simon
authors.forename: B T
authors.initials: BT
authors.lastname: Veering
authors.forename: R
authors.initials: R
authors.lastname: Stienstra
authors.forename: J W
authors.initials: JW
authors.lastname: van Kleef
authors.forename: S G P
authors.initials: SG
authors.lastname: Williams
authors.forename: G M
authors.initials: GM
authors.lastname: McGuire
authors.forename: A G L
authors.initials: AG
authors.lastname: Burm
mesh_terms: D000293:Adolescent; D000328:Adult; D000767:Anesthesia, Epidural; D002045:Bupivacaine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics*; D003903:Deuterium; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D000077554:Levobupivacaine; D008297:Male; D008875:Middle Aged
chemical_list: D000077554:Levobupivacaine; D003903:Deuterium; D002045:Bupivacaine