Development of New H1 Antihistamines: The Importance of Pharmacokinetics in the Evaluation of Safe and Therapeutically Effective Agents

Abstract

H 1 antihistamines are widely used in the treatment of allergic disorders. The CNS depressant and antimuscarinic effects of the first generation compounds limited their use in allergic disorders, and the second generation compounds were developed to reduce or eliminate these effects. However, the use of the first second generation H1 antihistamines, terfenadine and astemizole, under certain circumstances, was associated with adverse cardiac effects, which were occasionally fatal and they were withdrawn from the market. This review examines the pharmacokinetics of the second generation antihistamines and the impact of the pharmacokinetic properties on their efficacy and safety, particularly with regard to their effects on the central nervous and cardiovascular systems and their potential for interactions with concomitantly administered drugs and dietary components.

Drug interactions

“…Therefore, it would appear that the mechanisms for elimination of both drugs are mutually exclusive. Moreover, at a dose of 5 mg, cetirizine has no effect on the renal clearance of 120 mg of pseudoephedrine (and pseudoephedrine has no effect on the renal clearance of cetirizine), suggesting, at this dose, a lack of interaction of cetirizine with renal cation secretion (Whomsley and Strolin Benedetti, 2005).…”

“…Because transporters appear to play a key role in its disposition and as it is barely metabolized, fexofenadine has been the subject of many recent clinical and in vitro studies investigating its interactions with modulators of transport proteins. Azithromycin, erythromycin, itraconazole, ketoconazole, lopinavir, probenecid, ritonavir, St Johns wort (single dose), and verapamil all increase systemic exposure of fexofenadine (Whomsley and Strolin Benedetti, 2005). Although the interactions are certainly due to inhibition of fexofenadine transport, the mechanisms involved remain the subject of much debate.…”

“…Grapefruit juice can significantly reduce the oral absorption of fexofenadine, the active metabolite of terfenadine, probably through inhibition of OATP-A (Whomsley and Strolin Benedetti, 2005;Dresser et al, 2002;Dresser et al, 2005). The effect of grapefruit on fexofenadine is not only pharmacokinetic, but the pharmacodynamics of the drug are also modified: The size of histamine-induced wheal and flare were significantly larger when fexofenadine was administered with grapefruit or orange juices, compared to water (Duan, 2007).…”

Permeability—PAMPA

“…Benazepril is not part of the checkered paracellular set quite likely because it is an outlier in the study. The modest bioavailability of fexofenadine has been attributed partly to low intestinal permeability, because the Caco -2 cell permeability of the molecule is low (even in the presence of potent Pgp inhibitors) [202] . Based on the PAMPA data, the molecule would have been expected to have somewhat higher human bioavailability.…”

Advances in the molecular modeling and quantitative structure–activity relationship-based design for antihistamines

“…The most relevant of these adverse effects is sedation [6]. The development of second generation drugs, unable to cross the BBB, has effectively reduced this problem, so that practically they do not cause somnolence [7]. The drugs in the anti-H1 family are numerous; among the most commonly consumed are the following: cetirizine, loratadine, promethazine, quetiapine, cyclizine, cyproheptadine and doxylamine [8].…”