Effect of cyclodextrin infusion in a rat model of verapamil toxicity

Abstract

Sulfobutylether-β-cyclodextrin (SBE-CD) is a pharmaceutical excipient known to bind verapamil. After intravenous administration, clearance of SBE-CD approximates glomerular filtration rate. We hypothesized that SBE-CD would complex with verapamil in vivo, enhance renal elimination, and increase time to death in a rat model of verapamil toxicity. Ten Wistar rats were allocated to control or intervention groups. All received isoflurane anesthesia followed by verapamil infusion (32 mg/kg) over 1 hour. The control group received saline bolus 7.5 mL/kg at 5 minutes. The intervention group received SBE-CD infusion 7.5 mL/kg (2.25 g/kg) at 5 minutes. Heart rate, respiratory rate, oxygen saturation, and temperature were monitored. The primary endpoint was time to death measured separately as time to asystole and time to apnea. There was no benefit derived from cyclodextrin infusion. Average time to death was significantly longer in the control group as measured by time to apnea (P < 0.05). Control group survival was significantly better as measured by time to asystole and time to apnea (Breslow P < 0.05). SBE-CD infusion resulted in a shorter time to death measured by time to apnea and asystole. Preliminary work demonstrated no effect in isoflurane anesthetized rats receiving only SBE-CD bolus. Verapamil poisoned rats treated with 2.25 g/kg of SBE-CD showed increased toxicity. We propose that this effect was related to the large hyperosmolar CD infusion combined with verapamil-induced cardiogenic shock. Additional studies are warranted to clarify the mechanism of increased toxicity in our study and to assess for potential beneficial effects at lower SBE-CD concentrations.