Micro-pharmacokinetics of lidocaine and bupivacaine transfer across a myelinated nerve fiber

Vladimir Smrkolj; Domen Pregeljc; Hana Kavčič; Nejc Umek; Janez Mavri

doi:10.1016/j.compbiomed.2023.107375

Micro-pharmacokinetics of lidocaine and bupivacaine transfer across a myelinated nerve fiber

Comput Biol Med. 2023 Oct:165:107375. doi: 10.1016/j.compbiomed.2023.107375. Epub 2023 Aug 18.

Authors

Vladimir Smrkolj¹, Domen Pregeljc², Hana Kavčič³, Nejc Umek⁴, Janez Mavri⁵

Affiliations

¹ Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia; Laboratory of Computational Biochemistry and Drug Design, National Institute of Chemistry, Ljubljana, Slovenia.
² Department of Chemistry, Imperial College London, London, United Kingdom.
³ Clinical Department for Anesthesiology and Surgical Intensive Therapy of University Medical Center Ljubljana, Ljubljana, Slovenia; Department of Anesthesiology and Reanimatology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
⁴ Institute of Anatomy, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
⁵ Laboratory of Computational Biochemistry and Drug Design, National Institute of Chemistry, Ljubljana, Slovenia. Electronic address: janez.mavri@ki.si.

PMID: 37611421
DOI: 10.1016/j.compbiomed.2023.107375

Abstract

Background: The aim of the present study was to predict the time to onset and duration of action of two local anesthetics (lidocaine and bupivacaine) based on experimental dimensions of a typical nerve and experimental octanol/water partition coefficients.

Methods: We began our compilation of experimental data with a numerical solution of the Smoluchowski equation for the transfer of lidocaine and bupivacaine across the axon membrane in the region of the node of Ranvier (axolemma) and across the Schwann cell. The difference between the aqueous and lipid environments of the neuron was simulated by including the coordinate-dependent chemical potential. In the second step, the permeation rates calculated using the diffusion equation were used to solve a system of four ordinary differential equations. This approach allowed us to simulate the cellular environment for a longer time and to compare our model with pharmacokinetic properties (time to onset and duration of action) of local anesthetics from the literature. The behavior of local anesthetics under physiological conditions and in case of local acidosis was also simulated.

Results: We demonstrated that local anesthetics cross the axolemma in a time span of less than 1 μs. The time to onset of action, controlled by diffusion from the epineurium to an axon with a typical distance of 500 μm, was 167 s and 186 s for lidocaine and bupivacaine, respectively. The calculated half-life, which is a measure of the duration of action, was 41 min and 328 min for lidocaine and bupivacaine, respectively.

Conclusions: Duration of action is controlled by the storage capacity of lipophilic compartments around the axon, which is higher for bupivacaine but lower in local acidosis. For the latter case, the literature, including textbooks, provides a misinterpretation, namely that protonated species cannot penetrate the membrane.

Keywords: Diffusion; Local anesthetics; Micro-pharmacokinetics; Modeling; Time of onset.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anesthetics, Local / pharmacokinetics
Bupivacaine* / pharmacokinetics
Lidocaine* / pharmacokinetics
Nerve Fibers, Myelinated

Substances

Bupivacaine
Lidocaine
Anesthetics, Local