title: Brain mitochondrial drug delivery: influence of drug physicochemical properties.
abstract: OBJECTIVE
  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 (R(2) = 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Colorado Denver, 12850 E. Montview Blvd., Aurora, Colorado 80045, USA.
authors.forename: Shelley A
authors.initials: SA
authors.lastname: Durazo
authors.forename: Rajendra S
authors.initials: RS
authors.lastname: Kadam
authors.forename: Derek
authors.initials: D
authors.lastname: Drechsel
authors.forename: Manisha
authors.initials: M
authors.lastname: Patel
authors.forename: Uday B
authors.initials: UB
authors.lastname: Kompella
mesh_terms: D000305:Adrenal Cortex Hormones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D001921:Brain / Q000378:metabolism; D055598:Chemical Phenomena; D003198:Computer Simulation; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000502:physiology; D058990:Molecular Targeted Therapy; D011433:Propranolol / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012984:Software
chemical_list: D000305:Adrenal Cortex Hormones; D000319:Adrenergic beta-Antagonists; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011433:Propranolol