Some pharmacokinetic aspects of the lipophilic terfenadine and zwitterionic fexofenadine in humans

Abstract

Fexofenadine, an active metabolite of the second-generation histamine H1 receptor antagonist (antihistamine) terfenadine, does not have the disadvantage of QT prolongation. In addition, unlike first-generation antihistamines, it is associated with few CNS adverse effects. Chemically, fexofenadine has a zwitterionic structure that makes it an interesting molecule for use as an oral drug. Fexo-fenadine has negligible hepatic metabolism in humans, and is recovered mainly in the faeces in an unchanged form after oral administration. The absolute oral bioavailability of fexofenadine in humans is not known because of a lack of studies of intravenous administration of this agent. Its apparent elimination half-life (t1/2) ranges from 3 to 17 hours and is highly dependent on study design, i.e. the length of blood sampling. This large discrepancy might be associated with a 'flip-flop' phenomenon caused by slow absorption of the zwitterionic molecule. This review summarises the available literature related to the absorption, elimination and excretion of fexofenadine and terfenadine. Based on these data, the volume of distribution, t1/2 and oral bioavailability of fexofenadine in humans are estimated. Understanding these pharmacokinetic aspects of this drug might be very useful for medicinal chemists utilising fexofenadine/terfenadine as an example for designing zwitterionic compounds to combat cardiotoxicity and other issues related to basic and lipophilic molecules.