title: On the partition of ampholytes: application to blood-brain distribution.
abstract: Partition coefficients in the water-octanol, -cyclohexane, and -dichloromethane systems were determined as a function of pH for three non-zwitterionic ampholytes (nitrazepam, albendazole sulfoxide, and sulfadimidine) and three zwitterionic ampholytes (morphine, difloxacin, and niflumic acid). From known macro- and microprotonation constants in water, the concentration of cation, anion, neutral form, and zwitterion can be found, and partition coefficients can then be calculated for the partition of the neutral form in water to the neutral form in the organic solvent for all six compounds. These micropartition coefficients were then used to obtain descriptors for the neutral form in the general linear free energy (LFER) equation of Abraham. Knowledge of the descriptors enables a number of physicochemical and biochemical properties of the neutral form to be estimated; a detailed analysis is given of the estimation of the blood-brain distribution ratio for the process of going from the neutral form in blood to the neutral form in brain. A related procedure leads to an estimation of the distribution ratio for the process of going from the zwitterion in blood to the neutral form in brain.
authors.affiliation: Department of Chemistry, University College London, UK.
authors.forename: M H
authors.initials: MH
authors.lastname: Abraham
authors.forename: K
authors.initials: K
authors.lastname: Takács-Novák
authors.forename: R C
authors.initials: RC
authors.lastname: Mitchell
mesh_terms: D015766:Albendazole / Q000031:analogs & derivatives / Q000737:chemistry; D000890:Anti-Infective Agents; D001812:Blood-Brain Barrier / Q000502:physiology*; D002021:Buffers; D002939:Ciprofloxacin / Q000031:analogs & derivatives / Q000737:chemistry; D003510:Cyclohexanes; D024841:Fluoroquinolones; D006863:Hydrogen-Ion Concentration; D009020:Morphine / Q000737:chemistry; D009544:Niflumic Acid / Q000737:chemistry; D009567:Nitrazepam / Q000737:chemistry; D000442:Octanols; D004364:Pharmaceutical Preparations / Q000737:chemistry* / Q000378:metabolism; D012995:Solubility; D013329:Structure-Activity Relationship; D013418:Sulfamethazine / Q000737:chemistry; D014867:Water
chemical_list: D000890:Anti-Infective Agents; D002021:Buffers; D003510:Cyclohexanes; D024841:Fluoroquinolones; D000442:Octanols; D004364:Pharmaceutical Preparations; D014867:Water; D013418:Sulfamethazine; D009544:Niflumic Acid; D002939:Ciprofloxacin; C047225:difloxacin; D009020:Morphine; D009567:Nitrazepam; D015766:Albendazole; C027186:albendazole sulfoxide