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ANESTHETIC PHARMACOLOGY

The Pharmacokinetics and Pharmacodynamics of Propofol in a Modified Cyclodextrin Formulation (Captisol®) Versus Propofol in a Lipid Formulation (Diprivan®): An Electroencephalographic and Hemodynamic Study in a Porcine Model

Talmage D. Egan, MD^*, Steven E. Kern, PhD, Kenward B. Johnson, MD^*, and Nathan L. Pace, MD MStat^*

*Department of Anesthesiology, University of Utah School of Medicine; and Department of Pharmaceutics and Anesthesiology, University of Utah Schools of Pharmacy and Medicine, Salt Lake City, Utah

Address correspondence and reprint requests to Talmage D. Egan, MD, Department of Anesthesiology, University of Utah Health Sciences Center, Room 3C444, 30 N. 1900 E., Salt Lake City, UT 84132-2304. Address e-mail to talmage.egan{at}hsc.utah.edu

The currently marketed propofol formulation has a number of undesirable properties that are in part a function of the lipid emulsion formulation, including pain on injection, serious allergic reactions, and the support of microbial growth. A modified cyclodextrin-based formulation of propofol (sulfobutyl ether-ß-cyclodextrin) has been developed that may mitigate some of these formulation-dependent problems. However, reformulation may alter propofol’s pharmacologic behavior. Our aim in this study was to compare the pharmacokinetics and pharmacodynamics of propofol in the currently marketed lipid-based formulation with those of the novel cyclodextrin formulation. We hypothesized that the pharmacokinetics and pharmacodynamics of the propofol in cyclodextrin would be substantially similar to those of the propofol in lipid. Thirty-two isoflurane-anesthetized animals were instrumented with pulmonary artery, arterial, and IV catheters and were randomly assigned to receive either propofol in lipid or propofol in cyclodextrin by continuous infusion. Arterial blood samples for propofol assay were collected. The processed electroencephalogram, heart rate, mean arterial blood pressure, and cardiac output were measured continuously. The propofol formulations were compared by using model-independent analysis techniques. Combined kinetic/dynamic models were also constructed for simulation purposes. There were no significant differences in the pharmacokinetics or pharmacodynamics of the two propofol formulations. The simulations based on the combined pharmacokinetic/pharmacodynamic models confirmed the substantial similarity of the two formulations. The hypothesis that the propofol-in-cyclodextrin formulation would exhibit pharmacokinetic and pharmacodynamic behavior that was substantially similar to the propofol-in-lipid formulation was confirmed.

IMPLICATIONS: A modified cyclodextrin-based formulation of propofol has been developed that may mitigate some of the problems associated with propofol in lipid emulsion. However, reformulation of propofol may change its clinical characteristics. This study in a pig model showed that the novel propofol formulation was substantially similar to the lipid emulsion propofol formulation.

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