caa a22 4500 445314362 CHVBK 20180317142641.0 cr unu---uuuuu 170323e20111101xx s 000 0 eng 10.1007/s11095-011-0532-4 doi (NATIONALLICENCE)springer-10.1007/s11095-011-0532-4 Brain Mitochondrial Drug Delivery: Influence of Drug Physicochemical Properties [Elektronische Daten] [Shelley Durazo, Rajendra Kadam, Derek Drechsel, Manisha Patel, Uday Kompella] ABSTRACT: Purpose: To determine the influence of drug physicochemical properties on brain mitochondrial delivery of 20 drugs at physiological pH. Methods: The delivery of 8 cationic drugs (beta-blockers), 6 neutral drugs (corticosteroids), and 6 anionic drugs (non-steroidal anti-inflammatory drugs, NSAIDs) to isolated rat brain mitochondria was determined with and without membrane depolarization. Multiple linear regression was used to determine whether lipophilicity (Log D), charge, polarizability, polar surface area (PSA), and molecular weight influence mitochondrial delivery. Results: The Log D for beta-blockers, corticosteroids, and NSAIDs was in the range of −1.41 to 1.37, 0.72 to 2.97, and −0.98 to 2, respectively. The % mitochondrial uptake increased exponentially with an increase in Log D for each class of drugs, with the uptake at a given lipophilicity obeying the rank order cationic>anionic>neutral. Valinomycin reduced membrane potential and the delivery of positively charged propranolol and betaxolol. The best equation for the combined data set was Log % Uptake = 0.333 Log D + 0.157 Charge - 0.887 Log PSA + 2.032 (R2 = 0.738). Conclusions: Drug lipopohilicity, charge, and polar surface area and membrane potential influence mitochondrial drug delivery, with the uptake of positively charged, lipophilic molecules being the most efficient. Springer Science+Business Media, LLC, 2011 brain delivery nationallicence lipophilicity nationallicence membrane potential nationallicence mitochondrial delivery nationallicence polar surface area nationallicence CNPase : 2′ 3′-cyclic nucleotide 3′-phosphodiesterase nationallicence EDTA : ethylenediaminetetraacetic acid nationallicence F : explained variance/unexplained variance nationallicence FL2/FL1 : 590nm emission/525nm emission nationallicence LC-MS/MS : liquid chromatography tandem mass spectrometry nationallicence LDH : lactate dehydrogenase nationallicence Log D : Log distribution coefficient nationallicence Log P : Log partition coefficient nationallicence MW : molecular weight nationallicence N : number of molecules nationallicence NSAIDs : non-steroidal anti-inflammatory drugs nationallicence PBS : phosphate-buffered saline nationallicence pKa : acid dissociation constant nationallicence PSA : polar surface area nationallicence Q : charge nationallicence R2 : amount of variance in dependent variable that is explained by model nationallicence SD : standard deviation nationallicence SE : standard error of the estimate nationallicence α : polarizability nationallicence Durazo Shelley Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd., 80045, Aurora, Colorado, USA aut Kadam Rajendra Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd., 80045, Aurora, Colorado, USA aut Drechsel Derek Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd., 80045, Aurora, Colorado, USA aut Patel Manisha Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd., 80045, Aurora, Colorado, USA aut Kompella Uday Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd., 80045, Aurora, Colorado, USA aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/11(2011-11-01), 2833-2847 0724-8741 28:11<2833 2011 28 11095 https://doi.org/10.1007/s11095-011-0532-4 text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0532-4 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Durazo Shelley Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd., 80045, Aurora, Colorado, USA aut NATIONALLICENCE 700 1- Kadam Rajendra Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd., 80045, Aurora, Colorado, USA aut NATIONALLICENCE 700 1- Drechsel Derek Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd., 80045, Aurora, Colorado, USA aut NATIONALLICENCE 700 1- Patel Manisha Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd., 80045, Aurora, Colorado, USA aut NATIONALLICENCE 700 1- Kompella Uday Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd., 80045, Aurora, Colorado, USA aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/11(2011-11-01), 2833-2847 0724-8741 28:11<2833 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer