The gravity dependence of pharmacodynamics: the integration of lidocaine into membranes in microgravity

Abstract

To realize long-term manned space missions, e.g. to Mars, some important questions about pharmacology under conditions of different gravity will have to be answered to ensure safe usage of pharmaceuticals. Experiments on the International Space Station showed that the pharmacokinetics of drugs are changed in microgravity. On Earth, it is well known that the incorporation of substances into cellular membranes depends on membrane fluidity, therefore the finding that membrane fluidity is gravity dependent possibly has effects on pharmacodynamics of hydrophobic and amphiphilic substances in microgravity. To validate a possible effect of gravity on pharmacodynamics, experiments have been carried out to investigate the incorporation of lidocaine into plain lipid membranes under microgravity conditions. In microgravity, the induced increase in membrane fluidity associated with lidocaine incorporation is smaller compared to 1g controls. This experiment concerning the gravity dependence of pharmacodynamics in real microgravity clearly shows that the incorporation of amphipathic drugs into membranes is changed in microgravity. This might have significant impact on the pharmacology of drugs during long-term space missions and has to be investigated in more detail to be able to assess possible risks.

Fig. 1

a Normalized data of the changes in fluorescence polarization (FP) of the microgravity experiment and 1g ground reference. In both cases, upon addition of 16 mM lidocaine (start of mixing is indicated by arrow; mixing indicated by #₂; artifacts caused by moving air bubbles are marked by #₁), FP decreased. A reduced FP indicates a decrease in membrane viscosity or an increase in membrane fluidity. It is visible that, during microgravity, the increase membrane fluidity is less compared to 1g. The big spike was caused by the high g-load (24.2g) during the deployment of parachute. One datapoint (second 428) during the deployment was removed as an artifact due to the mechanical shock. b FP flight data compared to the acceleration profile (vector addition of all three axes x, y, and z). At the end of the flight, the average gravity increases again, the big spike indicates the opening of the parachute. With onset of gravity, FP slightly increased again. The dotted lines indicate 0g and 1g

Fig. 2

Statistical analysis of the data from the flight and 1g experiment. In 1g and in microgravity, 16 mM lidocaine significantly reduced fluorescence polarization (FP), so membrane fluidity is increased. A comparison between the lidocaine-induced changes of FP reveals a significant smaller decrease in microgravity compared to 1g. During the reentry phase, FP significantly increases again due to the general gravity dependence of membrane fluidity itself, but it does not recover to the values before the addition of lidocaine as this decreases FP. n (from left to right) = 98, 287, 98, 287, 94. Mean ± SD, Welch–analysis of variance and Games–Howell post hoc test. *p < .0005

Fig. 3

The change in vesicle size after the addition of 16 mM lidocaine measured in 1g after the flight. The untreated vesicle preparation of the rocket mission (not flown) was compared to the returned flight sample. The mean vesicle radius increased from 72.51 nm before the addition to 80.18 nm afterwards. n = 20. Boxplot: median, 25 and 75 percentile, whiskers min to max. Unpaired t test, *p < .0001

Fig. 4

Picture of the experiment hardware. (1) Rocket structure, (2) late access unit (LAU), and (3) experiment module. The experiment module fits into the pressure chamber of the LAU. The LAU is integrated into the structure housing shortly before launch

Fig. 5

Schematic of the experiment optical set-up and fluidic system. Vesicles and test substances are mixed and transferred to the sample cuvette. Fluorescence polarization is measured continuously for 525 s