Cerebrospinal Fluid Bioavailability and Pharmacokinetics of Bupivacaine and Lidocaine after Intrathecal and Epidural Administrations in Rabbits Using Microdialysis
- Rozenn Clement,
- Jean-Marc Malinovsky,
- Pascal Le Corre,
- Gilles Dollo,
- Francois Chevanne and
- Roger Le Verge
- Laboratoire de Pharmacie Galénique et Biopharmacie, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes, Rennes Cedex, France
Abstract
The aim of this work was to study the cerebrospinal fluid (CSF) bioavailability and pharmacokinetics of bupivacaine (BUP) and lidocaine (LID) administered separately in rabbits using microdialysis with retrodialysis calibration. Microdialysis probe and catheters were inserted under control of the view in the intrathecal or epidural spaces. The epidural disposition of BUP and LID after epidural administration of low (0.69 μM) and high (6.9 μM) doses was studied. Then, the intrathecal and plasma dispositions after separate intrathecal (0.2 μM) and epidural administration (6.9 μM) were investigated. The CSF binding of BUP and LID was linear in a range from 50 to 500 μg/ml, and the mean unbound CSF fraction at a concentration of 100 μg/ml was 39.3 ± 2.3% for BUP and 75.8 ± 7.7% for LID. Epidural and intrathecal disposition of BUP and LID showed a biexponential decline. After epidural administration, the CSF concentrations of BUP and LID were much higher than those in plasma. After intrathecal administration, the plasma concentrations were below the limit of quantitation. Although the absorption rate of BUP appeared higher than that of LID, the mean CSF bioavailability of epidural BUP and LID was 5.5 and 17.7%, respectively. The unexpectedly higher CSF bioavailability of LID, the less lipophilic drug, may result from the difference in the processes competing for drug epidural removal.
Footnotes
-
Send reprint requests to: Dr. Pascal Le Corre, Laboratoire de Pharmacie Galénique et Biopharmacie, Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1, 35043 Rennes Cedex, France. E-mail:Pascal.le-corre{at}univ-rennes1.fr
- Abbreviations:
- CSF
- cerebrospinal fluid
- BUP
- bupivacaine
- LID
- lidocaine
- RL
- relative loss
- RR
- relative recovery
- Cmax
- maximum total plasma concentration
- Cmax-epi
- maximum unbound epidural concentration
- Tmax
- peak plasma concentration time
- Tmax-csf
- peak CSF concentration time
- AUClast
- area under CSF concentration-time curves from the time of drug administration up to the last sampling point
- AUCcsf-it
- area under the unbound CSF concentration-time curve up to the last sampling point after intrathecal administration
- AUCcsf-epi
- area under the unbound CSF concentration-time curve up to the last sampling point after epidural administration
- AUCinf
- area under CSF concentration-time curves from the time of drug administration to infinity
- K10
- elimination rate constant
- K12 and K21
- distribution rate constants
- Ka
- absorption rate constant
- V1
- initial volume of distribution
- Vss
- steady-state volume of distribution
- Fcsf
- CSF bioavailability
- Cinj
- drug concentration of the solution injected
- CLE
- elimination clearance
- CLI
- intercompartmental clearance
-
- Received July 10, 1998.
- Accepted January 7, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
