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Pharmacokinetics and pharmacodynamics of the new propofol prodrug GPI 15715 in rats

Schywalsky, M.*; Ihmsen, H.*; Tzabazis, A.*; Fechner, J.*; Burak, E.; Vornov, J.; Schwilden, H.*

European Journal of Anaesthesiology (EJA): March 2003 - Volume 20 - Issue 3 - p 182-190
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Background and objective: We studied the pharmacokinetics and pharmacodynamics of GPI 15715 (Aquavan® injection), a new water-soluble prodrug metabolized to propofol by hydrolysis.

Methods: Nine adult male Sprague-Dawley rats (398 ± 31 g) received a bolus dose of 40 mg GPI 15715. The plasma concentrations of GPI 15715 and propofol were determined from arterial blood samples, and the pharmacokinetics of both compounds were investigated using compartment models whereby the elimination from the central compartment of GPI 15715 was used as drug input for the central compartment of propofol. Pharmacodynamics were assessed using the median frequency of the EEG power spectrum.

Results: A maximum propofol concentration of 7.1 ± 1.7 μg mL−1 was reached 3.7 ± 0.2 min after bolus administration. Pharmacokinetics were best described by two-compartment models. GPI 15715 showed a short half-life (2.9 ± 0.2 and 23.9 ± 9.9 min), an elimination rate constant of 0.18 ± 0.01 min−1 and a central volume of distribution of 0.25 ± 0.02 L kg−1. For propofol, the half-life was 1.9 ± 0.1 and 45 ± 7 min, the elimination rate constant was 0.15 ± 0.02 min−1 and the central volume of distribution was 2.3 ± 0.6 L kg−1. The maximum effect on the electroencephalogram (EEG) - EEG suppression for >4 s - occurred 6.5 ± 1.2 min after bolus administration and baseline values of the EEG median frequency were regained 30 min later. The EEG effect could be described by a sigmoid Emax model including an effect compartment (E0 = 16.9 ± 7.9 Hz, EC50 = 2.6 ± 0.8 μg mL−1, ke0 = 0.35 ± 0.04 min−1).

Conclusions: Compared with known propofol formulations, propofol from GPI 15715 showed a longer half-life, an increased volume of distribution, a delayed onset, a sustained duration of action and a greater potency with respect to concentration.

*University of Erlangen-Nuremberg, Department of Anaesthesiology, Erlangen, Germany;Guilford Pharmaceuticals, Baltimore, MD, USA

Correspondence to: Harald Ihmsen, Klinik für Anästhesiologie, Krankenhausstr. 12, D-91054 Erlangen, Germany. E-mail: Harald.Ihmsen@kfa.imed.uni-erlangen.de; Tel: +49 9131 85 39157; Fax: +49 9131 85 39161

Accepted for publication May 2002 EJA 1061

© 2003 European Society of Anaesthesiology