Abstract
Understanding the tissue distribution of phospholipids and glycerolipids in animal models enables promoting the pharmacokinetic study of drugs and related PK predictions. The measurement of lipid compositions in animal models, usually mice and rats, without a standardized approach hindered the accuracy of PBPK investigation. In this work, high resolution mass spectrometry was applied to profile the tissue distribution of phospholipids and glycerolipids in 12 organs/tissues of mice and rats. Using this method, not only the amounts of phospholipids and glycerolipids in each organ/tissue but also the fatty acid compositions were acquired. In order to explore the interspecies specificity of lipid distribution in different organs/tissues, three animal species including CD1 mice, NMRI mice, and Wister rats were used in this systematic study. Globally, more organ specificity was observed. It was found that the brain is the organ containing the most abundant phosphatidylserine lipids (PSs) in all three animal models, leading to brain tissues having the most concentrated acidic phospholipids. Diverse fatty acid compositions in each lipid class were clearly revealed. Certain tissues/organs also had a specific selection of unique fatty acid compositions, for example, unreferenced FA(18 : 2) in the brain. It turned out that the access of free fatty acids affects the incorporation of acyl chain in phospholipids and glycerolipids. In the analysis, ether lipids were also profiled with the observation of dominant ePEs in brain tissues. However, little interspecies difference was found for fatty acid constituents and tissues distribution of phospholipids and glycerolipids.
Highlights
Phospholipids and glycerolipids are major lipid constituents of cell membranes. ey are involved in many cellular processes in health and disease
Various diseases have been reported to correlate with lipid metabolism [1,2,3,4,5] and several studies revealed changes in lipid regulation in animal and human tissues for different diseases [6,7,8,9,10]. e primary function of the highly abundant phospholipids and glycerolipids though is to support the structure of the cellular membrane. e lipid composition of cell membranes and tissues plays an important role in determining the pharmacokinetics (PK) of drugs, in particular their tissue partitioning which to a large extent is controlled by the lipid components in the body tissues [11,12,13,14,15]. ere is great interest in accurate a priori predictions of drug-tissue partition coefficients based on the tissue composition in human or preclinical animal species15
Measurements using different methods and techniques may introduce a significant amount of bias into interspecies comparison and their corresponding PK predictions and different tissue dissection and storage conditions may lead to inaccuracies of lipid investigation. erefore, there is a need for a more systematic analysis of animal species and strain differences of tissue lipid constituents using the same analytical approach
Summary
Phospholipids and glycerolipids are major lipid constituents of cell membranes. ey are involved in many cellular processes in health and disease. Phospholipids and glycerolipids are major lipid constituents of cell membranes. Ere is great interest in accurate a priori predictions of drug-tissue partition coefficients based on the tissue composition in human or preclinical animal species. Based PK (PBPK) models, need to account for species differences in lipid constituents that determine drug-tissue distribution. Previous reports suggest the existence of species differences in the lipid tissue composition [16], lipid constituents in various animal strains have mostly been investigated individually in different studies using different protocols [17,18,19]. Erefore, there is a need for a more systematic analysis of animal species and strain differences of tissue lipid constituents using the same analytical approach. Shotgun lipidomics based on direct infusion was first introduced for complex lipid analysis using distinctive neutral loss scans [20,21,22,23,24]
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