Brain Mitochondrial Drug Delivery: Influence of Drug Physicochemical Properties
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.
KEY WORDSbrain delivery lipophilicity membrane potential mitochondrial delivery polar surface area
2′ 3′-cyclic nucleotide 3′-phosphodiesterase
explained variance/unexplained variance
590 nm emission/525 nm emission
liquid chromatography tandem mass spectrometry
- Log D
Log distribution coefficient
- Log P
Log partition coefficient
number of molecules
non-steroidal anti-inflammatory drugs
acid dissociation constant
polar surface area
amount of variance in dependent variable that is explained by model
standard error of the estimate
ACKNOWLEDGMENTS & DISCLOSURES
This work was supported in part by the NIH grants R01EY018940 (UBK), R01EY017533 (UBK), R01NS45748 (MP) and R01NS039587 (MP).
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