Micellar Partition Coefficient of Drugs as a Parameter to Estimate Blood-brain Barrier Penetration
Carlota O Rangel Yagui
Department of Pharmacy,
School of Pharmaceutical Sciences,
University of São Paulo
Av. Prof. Lineu Prestes, 580, Bl. 15, 05508-900,
São Paulo, Brazil
Abstract:
Penetration through Blood Brain Barrier (BBB) is one of the most critical pharmacokinetic issues in designing CNS active drugs and a concern in developing other classes of drugs, for which penetration would result in undesired CNS effects. The hydrophobicity of a solute measured by its logPo,w has been widely employed to model transmembrane permeability and the blood-brain equilibrium distribution ratio (logBB). However, there is some indication that Po,w is an unreliable predictor of drug penetration across the BBB. In this work, we evaluated the partition coefficient of some drugs in hexadecylphosphocholine (HDPC) micellar system, as well as its correlation with logBB. Based on solubility determinations (PBS and 6 mM HDPC) and micellar solubilization theory, Pmic,w values were calculated for the following drugs: Phenytoin, Salicylic Acid, Ibuprophen, Acetaminophen, Nalidixic Acid, Ofloxacin, Haloperidol, Oxicarbazepine, Diazepam, Pyrazinamide. Additionally, ClogP values were calculated. A linear correlation was observed between ClogPo,w and logBB, R2 = 0.50. Nevertheless, better correlation was observed between logPmic,w and logBB, R2 = 0.77, considering phenytoin and ofloxacin as outliers (for the whole set of drugs R2 = 0.01). The non-correlation between logPmic,w and logBB for these drugs might be explained since they are substrates for the efflux protein glycoprotein P.
