Abstract
IntroductionSulfobutylether-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.MethodsTwenty-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.ResultsVerapamil 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.ConclusionThe 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.
Highlights
Sulfobutylether-b-cyclodextrin (SBE-CD) is a pharmaceutical excipient known to bind verapamil
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)
We assessed the effect of a range of SBE-CD concentrations and identified 1 concentration that prolonged time to asystole
Summary
Sulfobutylether-b-cyclodextrin (SBE-CD) is a pharmaceutical excipient known to bind verapamil. Altering the number of substituent groups to the outer ring of the molecule significantly changes its characteristics, including its affinity for complexing with drugs and its osmolarity They are widely used as pharmaceutical excipients to modify drug solubility and stability.[1]. Rather than improving drug delivery, we are interested in the ability of cyclodextrins to enhance elimination of drug from the body This concept has proven feasible by the success of Cyclodextrins and Verapamil Toxicity sugammadex, a gamma-cyclodextrin that was modified to function as an intravenous reversal agent for rocuroniuminduced neuromuscular blockade following anesthesia.[2,3] Cyclodextrin molecules bind target drugs as a function of a complexation constant.[4] Modification of hydroxyl groups at the outer ring of the hydrophobic core enhances this property. We hypothesize that a favorable complexation constant, in addition to an equilibrium inequality driving the formula towards complexation, would allow binding and subsequent renal elimination of the target drug
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