Reply

We have read with great interest the letter from Suarez et al. [1]. Unfortunately, when we submitted our article, the most recent article from their group [2] was not yet published and we were unable to incorporate their results to our discussion. Their letter gives us the opportunity to improve the discussion on the points raised by their paper.

We do not agree with the statement that the tittle of our paper is misleading. It is no more misleading than the tittles from their previous papers [2–4] and we think that the words ‘implications for PK-PD’ are no more misleading than the word ‘significance’ used by Zamacona et al. [2]. We measured propofol binding to serum drawn from volunteers and to isolated proteins exactly as did these authors. We also measured propofol binding to red blood cells which appeared to bind half the propofol molecules in blood as it was previously shown [5].

We agree that propofol adsorption is time dependent and, because we never have been able to perform ultrafiltration in less than 15 min (total time between pipetting into the device and ultrafiltrate sampling) we used an alternative method. In fact, we tested different membranes including YMT membranes (the same as those used in the MPS1 system). In our lab, the latter membranes exhibited more than 20% binding after 30 min incubation.

In a study done in patients with a reduced albumin content, Suarez et al. found a 25% decrease in propofol binding [4]. This decrease is in accordance to our predictions from in vitro binding measurements. We totally agree with Suarez et al. when they state that propofol do not bind to the proteinic part of the lipoproteins. They used ultracentrifugation, which permits to obtain proteins in their integrity. However, these proteins are surrounded by their natural environment, which is lipidic in essence in the case of lipoproteins. However, the discrepancies between their results and ours may be explained by the fact that propofol is highly soluble in lipids. Therefore, propofol is not only bound to the lipidic part of lipoproteins but also propofol is solubilized by the lipids carried by these proteins. Moreover, because propofol is used as an emulsion in Intralipid®, this carrier system may represent a major component of transport. Then, the two approaches used by Suarez et al. on one hand, and by us on another hand, are complementary and allow to better understanding the process of binding and transport of propofol in blood.

In conclusion, we continue to assert that the first site for propofol binding in blood is the red cells. However, anaemia per se is unlikely to induce an increase in propofol free fraction. Conversely, hypoalbuminemia would have more important effects on binding. We missed the role of lipids in propofol transport, and Suarez et al. indirectly pointed out that effect. The carrier lipidic emulsion is certainly of major importance, especially in patients receiving long-term infusion for sedation. This factor remains to be studied.