Pharmaceutical Research

, 28:2833 | Cite as

Brain Mitochondrial Drug Delivery: Influence of Drug Physicochemical Properties

  • Shelley A. Durazo
  • Rajendra S. Kadam
  • Derek Drechsel
  • Manisha Patel
  • Uday B. Kompella
Research Paper



To determine the influence of drug physicochemical properties on brain mitochondrial delivery of 20 drugs at physiological pH.


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.


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).


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.


brain delivery lipophilicity membrane potential mitochondrial delivery polar surface area 



2′ 3′-cyclic nucleotide 3′-phosphodiesterase


ethylenediaminetetraacetic acid


explained variance/unexplained variance


590 nm emission/525 nm emission


liquid chromatography tandem mass spectrometry


lactate dehydrogenase

Log D

Log distribution coefficient

Log P

Log partition coefficient


molecular weight


number of molecules


non-steroidal anti-inflammatory drugs


phosphate-buffered saline


acid dissociation constant


polar surface area




amount of variance in dependent variable that is explained by model


standard deviation


standard error of the estimate





This work was supported in part by the NIH grants R01EY018940 (UBK), R01EY017533 (UBK), R01NS45748 (MP) and R01NS039587 (MP).

Supplementary material

11095_2011_532_MOESM1_ESM.pdf (413 kb)
Supplemental Figure 1 NSAID chromatogram containing a mixture of 5 μg/ml of each NSAID. Peaks: (1) indoprofen; (2) naproxen; (3) tolmetin; (4) ketoprofen; (5) flurbiprofen; (6) diclofenac; (7) mefenamic acid. (PDF 412 kb)


  1. 1.
    Good PF, Werner P, Hsu A, Olanow CW, Perl DP. Evidence of neuronal oxidative damage in Alzheimer’s disease. Am J Pathol. 1996;149(1):21–8.PubMedGoogle Scholar
  2. 2.
    Spina MB, Cohen G. Dopamine turnover and glutathione oxidation: implications for Parkinson disease. Proc Natl Acad Sci USA. 1989;86(4):1398–400.PubMedCrossRefGoogle Scholar
  3. 3.
    Geromel V, Kadhom N, Cebalos-Picot I, Ouari O, Polidori A, Munnich A, et al. Superoxide-induced massive apoptosis in cultured skin fibroblasts harboring the neurogenic ataxia retinitis pigmentosa (NARP) mutation in the ATPase-6 gene of the mitochondrial DNA. Hum Mol Genet. 2001;10(11):1221–8.PubMedCrossRefGoogle Scholar
  4. 4.
    Carmody RJ, Cotter TG. Oxidative stress induces caspase-independent retinal apoptosis in vitro. Cell Death Differ. 2000;7(3):282–91.PubMedCrossRefGoogle Scholar
  5. 5.
    Dunaief J. Iron induced oxidative damage as a potential factor in age-related macular degeneration: the Cogan Lecture. Invest Ophthalmol Vis Sci. 2006;47(11):4660–4.PubMedCrossRefGoogle Scholar
  6. 6.
    Primea TA, Blaikieb FH, Evansb C, Nadtochiyc SM, Jamesa AM, Dahma CC, et al. A mitochondria-targeted S-nitrosothiol modulates respiration, nitrosates thiols, and protects against ischemia-reperfusion injury. Proc Natl Acad Sci USA. 2009;106(26):10764–9.CrossRefGoogle Scholar
  7. 7.
    Zhao K, Zhao GM, Wu D, Soong Y, Birk AV, Schiller PW, et al. Cell-permeable peptide antioxidants targeted to inner mitochondrial membrane inhibit mitochondrial swelling, oxidative cell death, and reperfusion injury. J Biol Chem. 2004;279(33):34682–90.PubMedCrossRefGoogle Scholar
  8. 8.
    Neroev V, Archipova M, Bakeeva L, Fursova A, Grigorian E, Grishanova A, et al. Mitochondria-targeted plastoquinone derivatives as tools to interrupt execution of the aging program. 4. Age-related eye disease. SkQ1 returns vision to blind animals. Biochemistry (Moscow). 2008;73(12):1317–28.CrossRefGoogle Scholar
  9. 9.
    Horobin RW, Trapp S, Weissig V. Mitochondriotropics: a review of their mode of action, and their applications for drug and DNA delivery to mammalian mitochondria. J Control Release. 2007;121(3):125–36.PubMedCrossRefGoogle Scholar
  10. 10.
    Kamo N, Muratsugu M, Hongoh R, Kobatake Y. Membrane potential of mitochondria measured with an electrode sensitive to tetraphenyl phosphonium and relationship between proton electrochemical potential and phosphorylation potential in steady state. J Membr Biol. 1979;49(2):105–21.PubMedCrossRefGoogle Scholar
  11. 11.
    Kadam RS, Kompella UB. Influence of lipophilicity on drug partitioning into sclera, choroid-retinal pigment epithelium, retina, trabecular meshwork, and optic nerve. J Pharmacol Exp Ther. 2010;332(3):1107–20.PubMedCrossRefGoogle Scholar
  12. 12.
    Thakur A, Kadam RS, Kompella UB. Influence of drug solubility and lipophilicity on transscleral retinal delivery of six corticosteroids. Drug Metab Dispos. 2010;39(5):771–81.CrossRefGoogle Scholar
  13. 13.
    Castello PR, Drechsel DA, Patel M. Mitochondria are a major source of paraquat-induced reactive oxygen species production in the brain. J Biol Chem. 2007;282(19):14186–93.PubMedCrossRefGoogle Scholar
  14. 14.
    Sims NR, Anderson MF. Isolation of mitochondria from rat brain using Percoll density gradient centrifugation. Nat Protoc. 2008;3(7):1228–39.PubMedCrossRefGoogle Scholar
  15. 15.
    Drechsel DA, Patel M. Respiration-dependent H2O2 removal in brain mitochondria via the thioredoxin/peroxiredoxin system. J Biol Chem. 2010;285(36):27850–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Cossarizza A, Ceccarelli D, Masini A. Functional heterogeneity of an isolated mitochondrial population revealed by cytofluorometric analysis at the single organelle level. Exp Cell Res. 1996;222(1):84–94.PubMedCrossRefGoogle Scholar
  17. 17.
    Kadam RS, Kompella UB. Cassette analysis of eight beta-blockers in bovine eye sclera, choroid-RPE, retina, and vitreous by liquid chromatography-tandem mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2009;877(3):253–60.PubMedCrossRefGoogle Scholar
  18. 18.
    Lala N, Kumara J, Erdahla WE, Pfeiffera DR, Gaddc ME, Graffc G, et al. Differential effects of non-steroidal anti-inflammatory drugs on mitochondrial dysfunction during oxidative stress. Arch Biochem Biophys. 2009;490(1):1–8.CrossRefGoogle Scholar
  19. 19.
    Polster BM, Basanez G, Young M, Suzuki M, Fiskum G. Inhibition of Bax-induced cytochrome c release from neural cell and brain mitochondria by dibucaine and propranolol. J Neurosci. 2003;23(7):2735–43.PubMedGoogle Scholar
  20. 20.
    Dreisbach AW, Greif RL, Lorenzo BJ, Reidenberg MM. Lipophilic beta-blockers inhibit rat skeletal muscle mitochondrial respiration. Pharmacology. 1993;47(5):295–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Sionov RV, Cohen O, Kfir S, Zilberman Y, Yefenof E. Role of mitochondrial glucocorticoid receptor in glucocorticoid-induced apoptosis. J Exp Med. 2006;203(1):189–201.PubMedCrossRefGoogle Scholar
  22. 22.
    Smiley ST, Reers M, Mottola-Hartshorn C, Lin M, Chen A, Smith TW, et al. Intracellular heterogeneity in mitochondrial membrane potentials revealed by a J-aggregate-forming lipophilic cation JC-1. Proc Natl Acad Sci USA. 1991;88(9):3671–5.PubMedCrossRefGoogle Scholar
  23. 23.
    Johnson LV, Walsh ML, Bockus BJ, Chen LB. Monitoring of relative mitochondrial membrane potential in living cells by fluorescence microscopy. J Cell Biol. 1981;88(3):526–35.PubMedCrossRefGoogle Scholar
  24. 24.
    Krishnamurthy PC, Du G, Fukuda Y, Sun D, Sampath J, Mercer KE, et al. Identification of a mammalian mitochondrial porphyrin transporter. Nature. 2006;443(7111):586–9.PubMedGoogle Scholar
  25. 25.
    Zackova M, Kramer R, Jezek P. Interaction of mitochondrial phosphate carrier with fatty acids and hydrophobic phosphate analogs. Int J Biochem Cell Biol. 2000;32(5):499–508.PubMedCrossRefGoogle Scholar
  26. 26.
    Palmieri F. The mitochondrial transporter family (SLC25): physiological and pathological implications. Pflugers Arch. 2004;447(5):689–709.PubMedCrossRefGoogle Scholar
  27. 27.
    Garg P, Verma J, Roy N. In silico modeling for blood—brain barrier permeability predictions. Springer US: Drug Absorption Studies; 2008. p. 510–56.Google Scholar
  28. 28.
    Smith NF, Raynaud FI, Workman P. The application of cassette dosing for pharmacokinetic screening in small-molecule cancer drug discovery. Mol Cancer Ther. 2007;6(2):428–40.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Shelley A. Durazo
    • 1
  • Rajendra S. Kadam
    • 1
  • Derek Drechsel
    • 1
  • Manisha Patel
    • 1
  • Uday B. Kompella
    • 1
  1. 1.Department of Pharmaceutical SciencesUniversity of Colorado DenverAuroraUSA

Personalised recommendations