Alpha-tocopherol influences the lipid membrane affinity of desipramine in a pH-dependent manner.
Phopholipidosis is a lipid storage disorder caused by cationic amphiphilic drugs (CADs) characterized by the lysosomal accumulation of phospholipids and drug. alpha-Tocopherol (alpha-Toc) has a reversible effect on phospholipidosis in rats and cell culture. We studied the influence of alpha-Toc on the partitioning of the CAD desipramine in a liposome/buffer system using equilibrium dialysis with the following lipid compositions: egg phosphatidylcholine (PhC) or wheat germ phosphatidylinositol (PhI) or a combination of PhC, PhI and cholesterol, containing between 1.5 and 20% (mol per mol total lipids) of alpha-Toc, alpha-tocopherol acetate (alpha-TocAc), 2,2,5,7,8-pentamethyl-6-chromanol (PMC) or cholesterol. alpha-Toc (1.5%) enhanced the partition coefficient of neutral desipramine by up to 1.1 log units while it had no influence on the partitioning of the ionized compound. In the PhC liposome system, at pH 7.4 logD increased with increasing alpha-Toc concentrations but was unchanged at pH 4.5. Similar effects were found with PMC while alpha-TocAc or cholesterol, between 1.5 and 20%, had no influence on the partitioning of desipramine. From these results we postulate that in vivo, alpha-Toc could mediate a redistribution of CADs from lysosomal membranes (pH approximately 4.5) to membranes and lipoproteins at physiological pH.
Marenchino
Marco
M
Institute of Pharmaceutical Sciences, ETH Winterthurerstr 190, CH-8057, Zürich, Switzerland. stefanie.kraemer@pharma.ethz.ch
Alpstäg-Wöhrle
Andrea L
AL
Christen
Barbara
B
Wunderli-Allenspach
Heidi
H
Krämer
Stefanie D
SD
D000929:Antidepressive Agents, Tricyclic / Q000009:adverse effects / Q000737:chemistry*; D000975:Antioxidants / Q000008:administration & dosage / Q000737:chemistry*; D002784:Cholesterol / Q000737:chemistry; D002839:Chromans / Q000737:chemistry; D003891:Desipramine / Q000009:adverse effects / Q000737:chemistry*; D006863:Hydrogen-Ion Concentration; D008081:Liposomes; D008563:Membrane Lipids / Q000737:chemistry*; D010713:Phosphatidylcholines / Q000737:chemistry; D010716:Phosphatidylinositols / Q000737:chemistry; D011199:Potentiometry; D011433:Propranolol / Q000737:chemistry; D024505:Tocopherols; D014859:Warfarin / Q000494:pharmacology; D024502:alpha-Tocopherol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry*
D000929:Antidepressive Agents, Tricyclic; D000975:Antioxidants; D002839:Chromans; D008081:Liposomes; D008563:Membrane Lipids; D010713:Phosphatidylcholines; D010716:Phosphatidylinositols; D014859:Warfarin; C029141:2,2,5,7,8-pentamethyl-1-hydroxychroman; D002784:Cholesterol; D011433:Propranolol; D024502:alpha-Tocopherol; D024505:Tocopherols; D003891:Desipramine