Transmembrane pH-Gradient Liposomes To Treat Cardiovascular Drug Intoxication.
Summary of "Transmembrane pH-Gradient Liposomes To Treat Cardiovascular Drug Intoxication."
Injectable scavenging nanocarriers have been proposed as detoxifying agents when there are no specific antidotes to treat pharmacological overdoses. They act by capturing the drug in situ, thereby restricting distribution in tissues. In the clinic, the only systems used for that purpose are parenteral lipid emulsions, which are relatively inefficient in terms of uptake capacity. In this study, we investigated long-circulating liposomes with a transmembrane pH gradient as treatment for diltiazem intoxication. The unique ion-trapping properties of the vesicles toward ionizable compounds were exploited to sequester the drug in the bloodstream and limit its pharmacological effect. After in vitro optimization of the formulation, the in vivo scavenging properties of the liposomes were demonstrated by examining the drug's pharmacokinetics. The reduced volume of distribution and increased area under the plasma concentration versus time curve in animals treated with liposomes indicated limited tissue distribution. The vesicles exerted a similar but more pronounced effect on deacetyl-diltiazem, the principal active metabolite of the drug. This in vivo uptake of both drug and metabolite altered the overall pharmacological outcome. In rats receiving an intravenous bolus of diltiazem, the liposomes tempered the hypotensive decline and maintained higher average blood pressure for 1 h. The detoxifying action of liposomes was even stronger when the rats received higher doses of the drug via perfusion. In conclusion, the present work provided clear evidence that liposomes with a transmembrane pH gradient are able to change the pharmacokinetics and pharmacodynamics of diltiazem and its metabolite and confirmed their potential as efficient detoxifying nanocarriers.
Faculty of Pharmacy, University of Montreal, P.O. Box 6128, Downtown Station, Montreal, QC, Canada H3C 3J7.
This article was published in the following journal.
Name: ACS nano
Medical and Biotech [MESH] Definitions
Forms to which substances are incorporated to improve the delivery and the effectiveness of drugs. Drug carriers are used in drug-delivery systems such as the controlled-release technology to prolong in vivo drug actions, decrease drug metabolism, and reduce drug toxicity. Carriers are also used in designs to increase the effectiveness of drug delivery to the target sites of pharmacological actions. Liposomes, albumin microspheres, soluble synthetic polymers, DNA complexes, protein-drug conjugates, and carrier erythrocytes among others have been employed as biodegradable drug carriers.
Bacterial Proton-translocating Atpases
Membrane-bound proton-translocating ATPases that serve two important physiological functions in bacteria. One function is to generate ADENOSINE TRIPHOSPHATE by utilizing the energy provided by an electrochemical gradient of protons across the cellular membrane. A second function is to counteract a loss of the transmembrane ion gradient by pumping protons at the expense of adenosine triphosphate hydrolysis.
Centrifugation, Density Gradient
Separation of particles according to density by employing a gradient of varying densities. At equilibrium each particle settles in the gradient at a point equal to its density. (McGraw-Hill Dictionary of Scientific and Technical Terms, 4th ed)
A technique used to separate particles according to their densities in a continuous density gradient. The sample is usually mixed with a solution of known gradient materials and subjected to centrifugation. Each particle sediments to the position at which the gradient density is equal to its own. The range of the density gradient is usually greater than that of the sample particles. It is used in purifying biological materials such as proteins, nucleic acids, organelles, and cell types.
Artificial, single or multilaminar vesicles (made from lecithins or other lipids) that are used for the delivery of a variety of biological molecules or molecular complexes to cells, for example, drug delivery and gene transfer. They are also used to study membranes and membrane proteins.
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