Does The Formulation Of Propofol Affect Its PK-PD ?

J. Schüttler

Department of Anaesthesiology, University of Erlangen-Nuremberg, Erlangen, Germany

Introduction

Propofol, a potent intravenous sedative-hypnotic agent, which is widely used for general anaesthesia and sedation, is a substance with very slight solubility in water and, thus, is formulated as an oil-in-water emulsion. Possible disadvantages associated with the lipid emulsion formulation of propofol are the lipid intake, potential risk of infection due to microbial contamination and aggravated pain on injection. To overcome these problems, different appoaches were made during the last years, which can be roughly divided into three groups:

- lipid formulations with different solvents

- lipid-free propofol formulations

- lipid-free prodrugs which liberate propofol as metabolite

The development of such new propofol formulations raise the question whether the pharmacokinetics and pharmacodynamics of propofol are affected by its formulation.

Findings

Lipid formulations with different solvents

The first change in formulation was the introduction of Diprivan^Ò 2%, containing only half of the original solvent of Diprivan^Ò 1%. There were no differences in pharmacodynamics observed, whereas the volume of distribution was higher for Propofol 2%.^1,2 In the following, new propofol formulations with medium- and long-chain triglycerides (MCT/LCT) and different propofol dilutions (1%, 2% and 6%) were investigated in volunteers for anaesthesia^3,4 and in patients for sedation.^5-7 No differences were found with respect to pharmacokinetics and -dynamics, however the incidence of pain on injection was apparently less for the new formulations³. For two other new lipid carriers there were also found no effects on pharmacokinetics and –dynamics^8,9 but these formulations revealed undesired side effects, namely increased incidence of pain on injection⁹ and thrombophlebitis.⁸

Lipid-free propofol formulations

To date, investigations with lipid-free propofol have been performed only in animals. Dutta et al. administered lipid-free propofol in rats and found significant higher distribution volumes and a greater potency with respect to concentration compared to lipid emulsion.¹⁰ They could also demonstrate that these effects were probably caused by an increased pulmonary sequestration and a higher brain:plasma partition coefficient of the lipid-free drug.¹¹ When administering propofol in a lipid-free cyclodextrin formulation in mini-pigs, Egan et al. did not find significant differences.¹²

Propofol Prodrugs

A first propofol phosphate prodrug was studied only in animals with ambiguous results with respect to pharmacokinetics and with apparently less potency with respect to dose.¹³ The latest development is the new water-soluble prodrug GPI 15715 that is hydrolyzed by alkaline phosphatase to propofol, formaldehyde and phosphate. As prodrugs have to be metabolized first to liberate the active compound, they are inevitably characterized by a slower onset and a longer duration of effect. The interesting question is, however, whether the liberated propofol shows similar pharmacokinetics and ‑dynamics as propofol in a lipid emulsion. In volunteer studies with GPI 15715 and Diprivan^Ò we have found substantial differences, namely higher volumes of distribution and a higher potency (i.e. smaller EC₅₀ with respect to the EEG effect) for the propofol from GPI 15715.^14-16 In addition, propofol from GPI 15715 did not show a hysteresis between propofol plasma concentration and hypnotic effect. Whether these phenomena are an effect of the missing lipid carrier or whether they are caused by interaction with the parent drug is not yet clear.

Conclusion

Whereas for lipid propofol formulations the carrier has obviously no influence on the pharmacokinetics and -dynamics of propofol, lipid-free propofol formulations (which are not yet available for use in man) and propofol from prodrugs may exhibit a different pharmacokinetic/-dynamic profile compared to lipid emulsions.

Literature

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