A signal transduction pharmacodynamic model of the kinetics of the parasympathomimetic activity of low-dose scopolamine and atropine in rats

Itay Perlstein, David Stepensky, Wojciech Krzyzanski, Amnon Hoffman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

We used a novel pharmacokinetic-pharmacodynamic (PK-PD) approach that had been applied for signal transduction kinetics to investigate the kinetics of the parasympathomimetic effect of scopolamine and atropine in rats. The parasympathetic tone was assessed by continuous measurement of the power of the high frequency band (HF) of electrocardiogram (ECG) R-R intervals obtained by power spectral analysis (PSA) of heart rate variability (HRV). To overcome the inherent noise of the HRV-HF data and to quantitatively identify temporal changes in the autonomic tone, a new approach of stepwise regression of the cumulative HF data was applied. The elevation of the parasympathetic tone occurred after a significant lag time (>70 min) following scopolamine administrations [0.25 and 0.5 mg/kg intravenous (iv) bolus or infusion over 100 min], followed by a gradual return to the baseline levels. A similar lag time in parasympathetic stimulation was observed following iv bolus administration of atropine (0.1 mg/kg). The plasma drug concentration versus time data were linked to the response versus time data using a signal transduction pharmacodynamic model that was fitted simultaneously to all four experimental data sets. This PK-PD model resolved the significant discrepancy between the concentration versus time and the response versus time patterns and successfully described the kinetics of the parasympathetic stimulation obtained for different drugs and different rates of administration. This work paves the way for further PK-PD preclinical investigations in this field.

Original languageAmerican English
Pages (from-to)2500-2510
Number of pages11
JournalJournal of Pharmaceutical Sciences
Volume91
Issue number12
DOIs
StatePublished - Dec 2002

Keywords

  • Atropine
  • Heart rate variability
  • Pharmacodynamics
  • Pharmacokinetics
  • Power spectral analysis
  • Scopolamine
  • Signal transduction model

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