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Simultaneous Modeling of In Vivo and In Vitro Effects of Nondepolarizing Neuromuscular Blocking Drugs

Hikaru Hoshino, Eiko Furutani

TL;DR

This paper addresses the challenge of reconciling in vivo and in vitro effects of nondepolarizing neuromuscular blocking drugs (NDNBs) by evaluating three mechanism-based models of AChR activation: a two-site binding model, a competitive kinetic model with reciprocal gating, and a competitive kinetic model with cyclic gating. The authors develop a parameter-estimation framework that fits published EC50/γ_E (in vivo) and IC50/γ_I (in vitro) data for cisatracurium, vecuronium, and rocuronium, using a two-step process that first computes activated AChR fraction and then maps it to twitch strength, solved via numerical ODE methods. Results show the two-site binding model cannot simultaneously describe in vivo and in vitro data, while both competitive kinetic models can, with the cyclic gating scheme providing the best overall fit and a biologically plausible time course (<1 ms) of AChR activation; rocuronium's higher in vivo EC50 relative to in vitro predictions is explained by low in vivo ACh concentration and smaller site-selectivity. The work demonstrates a principled, mechanistic approach to cross-condition NDNB pharmacology and highlights how ACh dynamics and gating schemes shape in vivo potency, offering a framework for future refinements and applications.

Abstract

Nondepolarizing neuromuscular blocking drugs (NDNBs) are clinically used to produce muscle relaxation during general anesthesia. This paper explores a suitable model structure to simultaneously describe in vivo and in vitro effects of three clinically used NDNBs, cisatracurium, vecuronium, and rocuronium. In particular, it is discussed how to reconcile an apparent discrepancy that rocuronium is less potent at inducing muscle relaxation in vivo than predicted from in vitro experiments. We develop a framework for estimating model parameters from published in vivo and in vitro data, and thereby compare the descriptive abilities of several candidate models. It is found that modeling of dynamic effect of activation of acetylcholine receptors (AChRs) is essential for describing in vivo experimental results, and a cyclic gating scheme of AChRs is suggested to be appropriate. Furthermore, it is shown that the above discrepancy in experimental results can be resolved when we consider the fact that the in vivo concentration of ACh is quite low to activate only a part of AChRs, whereas more than 95% of AChRs are activated during in vitro experiments, and that the site-selectivity is smaller for rocuronium than those for cisatracurium and vecuronium.

Simultaneous Modeling of In Vivo and In Vitro Effects of Nondepolarizing Neuromuscular Blocking Drugs

TL;DR

This paper addresses the challenge of reconciling in vivo and in vitro effects of nondepolarizing neuromuscular blocking drugs (NDNBs) by evaluating three mechanism-based models of AChR activation: a two-site binding model, a competitive kinetic model with reciprocal gating, and a competitive kinetic model with cyclic gating. The authors develop a parameter-estimation framework that fits published EC50/γ_E (in vivo) and IC50/γ_I (in vitro) data for cisatracurium, vecuronium, and rocuronium, using a two-step process that first computes activated AChR fraction and then maps it to twitch strength, solved via numerical ODE methods. Results show the two-site binding model cannot simultaneously describe in vivo and in vitro data, while both competitive kinetic models can, with the cyclic gating scheme providing the best overall fit and a biologically plausible time course (<1 ms) of AChR activation; rocuronium's higher in vivo EC50 relative to in vitro predictions is explained by low in vivo ACh concentration and smaller site-selectivity. The work demonstrates a principled, mechanistic approach to cross-condition NDNB pharmacology and highlights how ACh dynamics and gating schemes shape in vivo potency, offering a framework for future refinements and applications.

Abstract

Nondepolarizing neuromuscular blocking drugs (NDNBs) are clinically used to produce muscle relaxation during general anesthesia. This paper explores a suitable model structure to simultaneously describe in vivo and in vitro effects of three clinically used NDNBs, cisatracurium, vecuronium, and rocuronium. In particular, it is discussed how to reconcile an apparent discrepancy that rocuronium is less potent at inducing muscle relaxation in vivo than predicted from in vitro experiments. We develop a framework for estimating model parameters from published in vivo and in vitro data, and thereby compare the descriptive abilities of several candidate models. It is found that modeling of dynamic effect of activation of acetylcholine receptors (AChRs) is essential for describing in vivo experimental results, and a cyclic gating scheme of AChRs is suggested to be appropriate. Furthermore, it is shown that the above discrepancy in experimental results can be resolved when we consider the fact that the in vivo concentration of ACh is quite low to activate only a part of AChRs, whereas more than 95% of AChRs are activated during in vitro experiments, and that the site-selectivity is smaller for rocuronium than those for cisatracurium and vecuronium.
Paper Structure (7 sections, 8 equations, 23 figures, 3 tables)

This paper contains 7 sections, 8 equations, 23 figures, 3 tables.

Table of Contents

  1. Introduction
  2. Methods
  3. Models of Neuromuscular Response
  4. Method of Parameter Estimation
  5. Results
  6. Discussion
  7. Conclusions

Figures (23)

  • Figure 1: Overall structure of the studied models consisting of the two steps: 1) calculation of the fraction of activated AChRs after the release of ACh and 2) calculation of the strength of the clinically observed muscle response to a stimulus.
  • Figure 2: Reciprocal scheme
  • Figure 3: Cyclic scheme
  • Figure 5: Two-site binding model (in vivo)
  • Figure 6: Two-site binding model (in vitro)
  • ...and 18 more figures