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S. A. Durazo, R. Kadam, D. Drechsel, M. Patel, U. B. Kompella; Unraveling the Mechanisms of Mitochondrial Uptake and Its Importance in Drug Targeting. Invest. Ophthalmol. Vis. Sci. 2010;51(13):2438.
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Mitochonodrial defects are hypothesized to underlie the pathologies of various eye disorders including retinal degenerations, optic neuropathies, and glaucoma. A critical rate limiting step in treating these disorders is targeted drug delivery to the mitochondria. As a first step in understanding the mechanisms of drug delivery to the mitochondria, the purpose of this study was to investigate the delivery of 20 drug molecules with varying lipophilicities and charges at physiological pH.
The delivery of 8 cationic drugs (beta-blockers), 6 neutral drugs (corticosteroids), and 6 anionic drugs (NSAIDs) was assessed using model mitochondria isolated from the brain of male Sprague Dawley rats. The Log D values for beta-blockers, corticosteroids, and NSAIDs were in the range of -2.02-1.2, 1.18-3.7, and -0.98-2, respectively. Drugs of each class were exposed as a separate cassette to freshly isolated mitochondrial preparations and the drug uptake was analyzed at the end of 1 h following separation of the free drug from the mitochondria. The drug uptake was quantified using high throughput assays for each cassette based on liquid chromatography tandem mass spectrometry (LC-MS/MS).
When the most lipophilic compound in each series was compared, it was observed that the positively charged compound had the highest percent uptake (propranolol: 79%), followed by the neutral compound (budesonide: 29%) and the negatively charged compound (mefanamic acid: 23%). Within each series, mitochondrial uptake increased with an increase in drug lipophilicity, with the correlations being more significant for the positively charged and neutral compounds (R2 > 0.8). Possibly due to a greater influence of membrane transporters, the correlation was poor for anionic compounds (R2 = 0.5). Molecular weight did not correlate well with mitochondrial drug delivery for a given class of drugs or for the entire dataset.
Molecular charge as well as lipophilicity influences targeted mitochondrial drug delivery, with positively charged, lipophilic molecules being most effective.
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