Research Articles
A Signal Transduction Pharmacodynamic Model of the Kinetics of the Parasympathomimetic Activity of Low-Dose Scopolamine and Atropine in Rats

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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. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association

Section snippets

INTRODUCTION

Sequences of cardiac interbeat intervals show spontaneous quasi-periodic fluctuations. This heart rate variability (HRV) is caused by the interaction of multiple regulatory influences on the sinus node, with most effects due to neural drive. HRV is decreased in various pathological states such as myocardial infarction1 and congestive heart failure.2 Prognosis of patients with low HRV following myocardial infarction is poor.3,4 This finding led to a clinical approach of elevating HRV by

Animals

Male Sabra rats weighing 300–350 g were housed separately in plastic cages and were maintained in a 12-h light/dark cycle with food and water available ad libitum. The project adhered to the principles of Laboratory Animal Care (NIH publication no. 85-23, revised 1985).

Transmitter Implantation

To minimize stress involved with data collection, a telemetric monitoring system was implanted in the peritoneal cavity while the animals were anesthetized [by intraperitoneal (ip) injection of 50 mg/kg ketamine and 10 mg/kg

Pharmacokinetics

The concentration versus time data of scopolamine followed the two-compartment open PK model with a rapid distribution phase (t1/2 alpha = 2 min) succeeded by a relatively short elimination phase (t1/2 beta = 18 min). The concentration versus time profile of atropine also followed the two-compartment model, but with much longer elimination phase (t1/2 beta = 52 min). The major PK parameters of both drugs are summarized in Table 1.

Pharmacodynamics

The temporal cumulative approach enabled the quantification of the HF

DISCUSSION

HRV is caused by the interaction of multiple regulatory influences on the sinus node, with most effects due to neural drive, and the HRV tachogram reflects the sum of all the different interactions. PSA is a well-established technique for frequency domain analysis of HRV that enables the division of the entire variability into separate frequencies and the identification of the effect of the interacting components.4,24 Thus, PSA provides the means to noninvasively determine neural drive by

ACKNOWLEDGEMENTS

The authors thank Dr. Joshua Backon for his valuable suggestions. Prof. A. Hoffman is affiliated with the David R. Bloom Center of Pharmacy. This work is part of the Ph.D. dissertation of I. Perlstein.

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