Lipophilicity and hydrogen-bonding capacity of H1-antihistaminic agents in relation to their central sedative side-effects

Abstract Modern non-sedating histamine H 1 -receptor antagonists (e.g. terfenadine, temelastine, cetirizine, astemizole) are considered to be devoid of CNS side-effects because, as a result of their physicochemical properties, they do not cross the blood-brain barrier (BBB) in sufficient amounts. In the present study lipophilicity parameters considered to be of importance for brain penetration capability (such as log P oct , log D oct,7.4 , Δ log P and ∧ alkane ) were determined for a series of structurally different sedating and non-sedating histamine H 1 -receptor antagonists. These parameters were obtained from log P oct and log P alk values measured by centrifugal partition chromatography (CPC), a new and efficient method for measuring partition coefficients. From the lipophilicity data obtained it appears that the (non)-sedative effects of antihistamines cannot be correctly accounted for by brain penetration models that use only H-bonding (Δ log P) or hydration capacity (∧ alkane ) as a parameter. Indeed, in this series of usually basic H 1 -blockers, ionization also appears to play an important role. We conclude that sedative effects displayed by antihistamines are better explained by the parameter log D oct,7.4 , the octanol/water distribution coefficient of both neutral and ionized species at pH 7.4. For neural organic compounds it was found that brain penetration is highest if they have a log P oct value of approximately 2 (‘principle of minimal hydrophobicity’). Our data suggest that this principle is also applicable to ionizable drugs when log D oct,7.4 is used instead of log P oct . A tentative qualitative model for designing antihistamines without CNS side-effects is presented.