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Lipophilicity and hydrogen-bonding capacity of H-1-antihistaminic agents in relation to their central sedative side-effects

Terlaak, A. M.
Tsai, Ruey-Shiuan
Denkelder, G. M. D. O.
Testa, Bernard
Timmerman, H.
Published in European Journal of Pharmaceutical Sciences. 1994, vol. 2, no. 5-6, p. 373-384
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,D-7,D-4, Delta log P and boolean 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 (Delta log P) or hydration capacity (boolean AND(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 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
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TERLAAK, A. M. et al. Lipophilicity and hydrogen-bonding capacity of H-1-antihistaminic agents in relation to their central sedative side-effects. In: European Journal of Pharmaceutical Sciences, 1994, vol. 2, n° 5-6, p. 373-384.

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Deposited on : 2010-08-06

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