Clinical pharmacology of H1-antihistamines in the skin.

The extent of the distribution of H(1)- antihistamines into the skin and H(1)-antihistamine activity in the skin are clinically relevant in the treatment of allergic skin disorders. In a prospective, randomized, double-blind, parallel-group, multiple-dose study, we gave fexofenadine 180 mg, loratadine 10 mg, or chlorpheniramine 8 mg to 21 men (7 in each group). Before dosing and at 1, 3, 6, 9, and 24 hours after the first antihistamine dose as well as at 168, 192, and 216 hours after the first dose (ie, 12, 36, and 60 hours after the seventh and last consecutive daily H(1)-antihistamine dose), we measured fexofenadine, loratadine, or chlorpheniramine concentrations in plasma and in skin tissue samples obtained through use of punch biopsies, along with suppression of histamine-induced skin wheals and flares. Loratadine metabolites, including desloratadine and its metabolites, were not measured, and chlorpheniramine metabolites were not measured. All 21 participants completed the study. Skin/plasma fexofenadine ratios ranged from 1.2 +/- 0.5 at 1 hour to 110 +/- 74 at 24 hours, and skin fexofenadine concentrations exceeded loratadine and chlorpheniramine skin concentrations at each test time. This was reflected in significant wheal and flare suppression by fexofenadine in comparison with loratadine at 3 hours and in comparison with chlorpheniramine at 6 and 9 hours (wheal) and from 3 to 24 hours and at 192 hours (flare). Compared with fexofenadine, loratadine significantly suppressed the wheal at 192 hours, and compared with chlorpheniramine, it significantly suppressed the wheal at 9 hours and the flare at 24 and 192 hours. At no time did chlorpheniramine suppress the wheal or flare significantly more than fexofenadine or loratadine. In skin disorders for which H(1)-antihistamines are recommended, these results support the use of fexofenadine or loratadine, and they indicate the need for reexamination of the use of chlorpheniramine.