LIPOPHILICITY AND HYDROGEN-BONDING CAPACITY OF H-1-ANTIHISTAMINIC AGENTS IN RELATION TO THEIR CENTRAL SEDATIVE SIDE-EFFECTS

Modern non-sedating histamine H-1-receptor antagonists (e.g. terfenadi ne, temelastine, cetirizine, astemizole) are considered to be devoid o f CNS side-effects because, as a result of their physicochemical prope rties, they do not cross the blood-brain barrier (BBB) in sufficient a mounts. In the present study lipophilicity parameters considered to be of importance for brain penetration capability (such as log P-oct, lo g D-oct,D-7,D-4, Delta log P and boolean AND(alkane)) were determined for a series of structurally different sedating and non-sedating hista mine H-1-receptor antagonists. These parameters were obtained from log P-oct and log P-alk values measured by centrifugal partition chromato graphy (CPC), a new and efficient method for measuring partition coeff icients. 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 (Delta log P) or hydration capacity (boolean AND(alkane)) as a parameter. Indeed, in th is series of usually basic H-1-blockers, ionization also appears to pl ay an important role. We conclude that sedative effects displayed by a ntihistamines are better explained by the parameter log D-oct.7.4, the octanol/water distribution coefficient of both neutral and ionized sp ecies at pH 7.4. For neural organic compounds it was found that brain penetration is highest if they have a logP(oct) value of approximately 2 ('principle of minimal hydrophobicity'). Our data suggest that this principle is also applicable to ionizable drugs when logD(oct7.4) is used instead of logP(oct). A tentative qualitative model for designing antihistamines without CNS side-effects is presented.