Serum protein binding of histamine H 1-antagonists. A comparative study on the serum protein binding of a sedating ([ 3H]mepyramine) and a non-sedating H 1-antagonist ([ 3H]loratadine)

Abstract

Nowadays classical histamine H 1-receptor antagonists (antihistamines) are relatively rarely used in therapy against allergic disorders, mainly because they are able to penetrate the central nervous system (CNS) and induce subsequently unwanted side effects (most importantly sedation). In contrast, several modern H 1-antagonists have been claimed not to penetrate the CNS and lack the sedating properties. In this study, human serum protein binding, one of the properties which may influence brain penetration of H 1-antagonists, has been investigated by comparing the sedating H 1-antagonist [ 4H]mepyramine with the non-sedating H 1-antagonist [ 1H]loratadine. It is shown that human serum albumin (HSA) binding and total serum protein binding of [ 1H]mepyramine is low at therapeutic levels and at physiological pH (<30% bound) and strongly depends on the ionization state of this compound (p K d = 8.92). Our results demonstrate tha the unprotonated form of mepyramine in particular binds to serum proteins. This conclusion is supported by further results from plain HSA binding experiments, in this study, on six other unlabeled. ‘classical’ H 1-antagonists (i.e., diphenhydramine, chlorpheniramine, dimethindene, imipramine, azatadine, descarbocthoxyloratadine). On the other hand, the modern non-sedating H 1-antagonist loratadine (log P oct=4.40) binds to a high level to serum proteins at therapeutic levels (>95% bound). Our results further indicate that the main determinants of HSA binding for H 1-antagonists are lipophilicity and acid-base properties as expressed by log P and p K d, re (both included in the parameter log D oct). However, hydrogen bonding capacity ( Δlog P) is not correlated to serum protein bin series of H 1-antagonists investigated. We further propose that highly lipophilic non-sedating H 1-antagonists (i.e., loratadine, terfenadine, astemizole, temelastine) probably have a low extraction ratio in the brain due to the tight lipoid blood brain barrier and a relatively high extraction ratio in the porous peripheral tissues.