Details

Autor(en) / Beteiligte

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

Titel

Brain Mitochondrial Drug Delivery: Influence of Drug Physicochemical Properties

Ist Teil von

• Pharmaceutical research, 2011-11, Vol.28 (11), p.2833-2847

Ort / Verlag

Boston: Springer US

Erscheinungsjahr

2011

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (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.