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 1 g 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.

How the space environment influences organisms: an astrobiological perspective and review

“…For example, the fluidity of cell membranes is increased in microgravity (Sieber et al ., 2014) that affects membrane proteins’ functionality, such as membrane channel conductance (Sieber et al ., 2016; Kohn et al ., 2017). Due to the increase in membrane fluidity, drugs’ pharmacokinetic (incorporation of amphipathic drugs into membranes) are changed in microgravity (Kohn and Hauslage, 2019). It is also observed that the bacterial virulence, pathogenicity and resistance to antibiotics increase in space microgravity conditions (Wilson et al ., 2008).…”

“…Higher concentrations of antibiotics are required to inhibit bacterial growth in microgravity. This is probably due to the lower transport rate (mass transport is limited to diffusion) and changes in cell proliferation, membrane permeability, rate and morphology (Klaus et al ., 1997, 2004; Kacena and Todd, 1999; Sieber et al ., 2014; Zea et al ., 2016, 2017; Kohn et al ., 2017; Aunins et al ., 2018; Kohn and Hauslage, 2019). In a study with the halophilic archaeon, Haloarcula argentinensis under simulated microgravity condition (clinostat), an increase in the activity of antibiotic efflux pumps resulting in the development of multi-drug resistance to antibiotics, such as augmentin, norfloxacin, tobramycin and cefoperazone was observed (Thombre et al ., 2017).…”

Drug discovery and development: the final frontier

“…This supports a membrane‐mediated effect for at least part of lidocaine's action. The effect on anti‐arrhythmic and local anaesthetic actions is not known, but further implies that pharmacodynamics may change in microgravity …”

Harnessing the Space Environment for the Discovery and Development of New Medicines

“…Lastly, it is important to consider both pharmacokinetic and pharmacodynamic aspects of drugs in space which has also featured in several excellent reviews (Zea 2015;Kast et al 2017;Braddock et al 2019a;Blue et al 2019b). A further recent study has investigated the effect of gravity on the integration of the anesthetic lidocaine into plain lipid membranes (Kohn and Hauslage 2019). In μG, it was shown that the induced increase in membrane fluidity associated with lidocaine incorporation is small when compared with 1 g controls suggesting that incorporation of amphipathic drugs is changed.…”