Dose-dependent response to cyclodextrin infusion in a rat model of verapamil toxicity

Abstract

Introduction: Sulfobutylether-β-cyclodextrin (SBE-CD) is a pharmaceutical excipient known to bind verapamil. Following intravenous administration, clearance of SBE-CD approximates glomerular filtration rate. We hypothesized that infusion of SBE-CD would increase time to asystole in a rat model of verapamil toxicity in a dose-dependent manner. The objective was to demonstrate the effect of a range of SBE-CD concentrations in a rat model of verapamil toxicity.

Methods: Twenty-five Wistar rats were allocated to control or 1 of 4 intervention groups. All received ketamine and diazepam anesthesia followed by verapamil infusion 32 mg/kg/h. The verapamil infusion for the intervention groups was premixed with SBE-CD in a 1:1, 1:2, 1:4, or 1:8 molar ratio (verapamil to SBE-CD). The control group infusion did not contain SBE-CD. Additional saline or water was added to the infusion so that the total volume infused was the same across groups, and the osmolality was maintained as close to physiologic as possible. Heart rate, respiratory rate, and temperature were monitored. The primary endpoint was time to asystole.

Results: Verapamil coinfused with SBE-CD in a molar ratio of 1:4 resulted in prolonged time to asystole compared to control (21.2 minutes vs 17.6 minutes, P < 0.05). There were no differences in time to asystole between control and any other intervention group. There was no significant difference in time to apnea between control and any intervention group. We assessed the effect of a range of SBE-CD concentrations and identified 1 concentration that prolonged time to asystole. Mechanisms that may explain this effect include optimal volume expansion with a hyperosmolar cyclodextrin containing solution, complexation of verapamil within the hydrophobic cyclodextrin pore, and/or complexation within micelle-like aggregates of cyclodextrin. However, mechanistic explanations for the observed findings are speculative at this point.

Conclusion: The 1:4 verapamil to SBE-CD concentration was modestly effective with SBE-CD concentrations above and below this range demonstrating nonstatistically significant improvements in time to asystole.

Figure 1

a, Time to asytole represented as absolute time ± standard error (SE). The 1:4 group time to asystole (*) was significantly prolonged compared to control (21.2 vs 17.6 minutes, P < 0.05). b, Time to apnea represented as absolute time ± SE. There was no significant difference between control and intervention groups. c, Baseline heart rate with 95% confidence interval (CI). There was no significant difference between control and intervention groups. d, Baseline respiratory rate with 95% CI. There was significant variability between control and intervention groups 2 (mean difference 18.2, 95% CI 4.7–31.7, P < 0.05) and 4 (mean difference 21.5, 95% CI 7.9–35, P < 0.05).

Figure 2

Normalized heart rate versus time to asystole for control and group 4 (1:4 verapamil to sulfobutylether-β-cyclodextrin). Values are indicated as mean normalized heart rate ± standard error (vertical error bars). Measurements are plotted from the beginning of drug infusion and at 25% increments of time to asystole. The horizontal error bars denote the variability in time to asystole between groups. Mean heart rate did not differ between groups. Time to asystole was significantly shorter in the control group (17.6 vs 21.2 minutes, P < 0.05).