PHARMACOKINETIC-PHARMACODYNAMIC RELATIONSHIPS OF H-1-ANTIHISTAMINES

Histamine H-1-receptor antagonists are reversible, competitive inhibit ors of the actions of histamine, a critical mediator in the pathophysi ology of the allergic response. This review is mainly devoted to secon d generation antihistamines that possess a low sedation potential comp ared with first generation compounds, The pharmacokinetic and pharmaco dynamic data of 10 compounds have been updated, Some values are lackin g for drugs under development, but also for older antihistamines. Ther eafter, pharmacokinetic-pharmacodynamic relationships are reported fro m published or original documents. A linear pharmacokinetic-pharmacody namic relationship has been found for acrivastine, astemizole, cetiriz ine, ebastine and terfenadine, whereas nonlinear relationships have be en calculated for ebastine (in the dog), levocabastine, mizolastine, n oberastine and terfenadine, It must be concluded that this type of app roach for therapeutic optimisation is very fruitful and may enable lar ge numbers of clinical studies to be avoided. Trends for the future in clude: (i) in vitro binding studies with the human H-1-receptor obtain ed by molecular biology; (ii) the characterisation of the cytochromes P450 responsible for the biotransformation of antihistamines; (iii) th e calculation of the pharmacokinetic-pharmacodynamic relationship in h ealthy individuals; and (iv) prospective effect-controlled clinical st udies.