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Original article
Population Pharmacokinetics of Amitriptyline After Intrathecal, Epidural, and Intravenous Administration in Sheep
  1. Maja Ratajczak-Enselme, PharmD, PhD*,†,
  2. Nicolas Grégoire, PharmD‡,
  3. Jean-Pierre Estebe, MD, PhD†,§,
  4. Gilles Dollo, PharmD, PhD*,†,
  5. F. Chevanne, BS*,
  6. David Bec, BS§,
  7. Claude Ecoffey, MD†,§,
  8. William Couet, PharmD, PhD‡ and
  9. Pascal Le Corre, PharmD, PhD*,†
  1. From the *Faculté des Sciences Pharmaceutiques et Biologiques, Université de Rennes 1, and INSERM U1085; and †Service Hospitalo-Universitaire de Pharmacie, CHU Rennes, Rennes; ‡INSERM U1070 and Faculté de Médecine et de Pharmacie, Université de Poitiers, Poitiers; and §Département d'Anesthésie 2, Faculté de Médecine, Université de Rennes 1, Rennes, France
  1. Address correspondence to: Jean-Pierre Estebe, MD, PhD, Department of Anesthesiology, University Hospital of Rennes, Rue Henri Le Guilloux 35033, Rennes, France (e-mail: jean-pierre.estebe{at}chu-rennes.fr).

Abstract

Background Amitriptyline (AMI) is a lipophilic, tricyclic antidepressant with analgesic properties that could potentially be used for epidural (EPI) analgesia. However, no pharmacokinetic data are available for AMI in spinal spaces. The objective of this study was to evaluate the spinal disposition and intrathecal (IT) bioavailability of AMI after IT and EPI administration.

Methods Six Lacaune ewes received 3 consecutive administrations of AMI. They initially received 10 mg of AMI administered intravenously, then 5 mg of AMI administered intrathecally, and 50 mg of AMI injected into the EPI space. Consecutive administrations were separated by intervals of 2 hours. A simultaneous microdialysis technique was used to determine the EPI and IT concentrations of AMI. Population analysis with S-ADAPT software was used to evaluate the pharmacokinetic parameters.

Results Following intravenous administration, the clearance and central compartment (V c) in plasma were 1.32 L/min and 147 L, respectively. Concentration-time profiles for the IT and EPI compartments were highly variable after transmeningeal diffusion. The IT V c after IT administration and the EPI V c after EPI administration were 2.4 and 48.9 mL, respectively. Less AMI transferred from the EPI to the IT space than from the IT to the EPI compartment, with bioavailabilities of 1.3% and 55%, respectively.

Conclusions Simultaneous population analysis for AMI demonstrated differences in EPI and IT pharmacokinetics following the EPI and IT administration of this drug. The IT bioavailability of AMI after EPI administration is relatively low.

https://doi.org/10.1097/AAP.0000000000000322

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    Footnotes

    • F. Chevanne is deceased.

    • No funding was received for this study.

      The authors declare no conflict of interest.

      Author Contributions: M.R.-E., J.-P.E., G.D., F.C., D.B., and P.L.C.: designed the study, performed the experiment, and oversaw data collection and verification; M.R.-E., P.L.C., N.G., and W.C.: analyzed and interpreted the data; M.R.-E., J.-P.E., N.G., C.E., and P.L.C.: wrote the initial draft. All authors critically ensured the accuracy of the data and analysis, reviewed the draft, and approved the final version of the manuscript for submission.

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