Skip to main content

Advertisement

SpringerLink
Log in

Brain Mitochondrial Drug Delivery: Influence of Drug Physicochemical Properties

  • Research Paper
  • Published:
Pharmaceutical Research Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

CNPase:

2′ 3′-cyclic nucleotide 3′-phosphodiesterase

EDTA:

ethylenediaminetetraacetic acid

F:

explained variance/unexplained variance

FL2/FL1:

590 nm emission/525 nm emission

LC-MS/MS:

liquid chromatography tandem mass spectrometry

LDH:

lactate dehydrogenase

Log D:

Log distribution coefficient

Log P:

Log partition coefficient

MW:

molecular weight

N:

number of molecules

NSAIDs:

non-steroidal anti-inflammatory drugs

PBS:

phosphate-buffered saline

pKa:

acid dissociation constant

PSA:

polar surface area

Q:

charge

R2 :

amount of variance in dependent variable that is explained by model

SD:

standard deviation

SE:

standard error of the estimate

α:

polarizability

REFERENCES

  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.

    PubMed  CAS  Google Scholar 

  2. Spina MB, Cohen G. Dopamine turnover and glutathione oxidation: implications for Parkinson disease. Proc Natl Acad Sci USA. 1989;86(4):1398–400.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  4. Carmody RJ, Cotter TG. Oxidative stress induces caspase-independent retinal apoptosis in vitro. Cell Death Differ. 2000;7(3):282–91.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  14. Sims NR, Anderson MF. Isolation of mitochondria from rat brain using Percoll density gradient centrifugation. Nat Protoc. 2008;3(7):1228–39.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  20. Dreisbach AW, Greif RL, Lorenzo BJ, Reidenberg MM. Lipophilic beta-blockers inhibit rat skeletal muscle mitochondrial respiration. Pharmacology. 1993;47(5):295–9.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  26. Palmieri F. The mitochondrial transporter family (SLC25): physiological and pathological implications. Pflugers Arch. 2004;447(5):689–709.

    Article  PubMed  CAS  Google Scholar 

  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. 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.

    Article  PubMed  CAS  Google Scholar 

Download references

ACKNOWLEDGMENTS & DISCLOSURES

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

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd., Aurora, Colorado, 80045, USA

    Shelley A. Durazo, Rajendra S. Kadam, Derek Drechsel, Manisha Patel & Uday B. Kompella

Authors
  1. Shelley A. Durazo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rajendra S. Kadam
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Derek Drechsel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Manisha Patel
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Uday B. Kompella
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Uday B. Kompella.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

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)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Durazo, S.A., Kadam, R.S., Drechsel, D. et al. Brain Mitochondrial Drug Delivery: Influence of Drug Physicochemical Properties. Pharm Res 28, 2833–2847 (2011). https://doi.org/10.1007/s11095-011-0532-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11095-011-0532-4

KEY WORDS

Search

Navigation