Changes in pH differently affect the binding properties of histamine H1 receptor antagonists
Abstract
We investigated the effect of acidic pH, a condition that can be encountered during inflammation accompanying allergic reaction, on the binding properties of histamine H1 receptor antagonists, including levocetirizine ((2-(4-[(R)-(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl)ethoxy)acetic acid; Xyzal ), fexofenadine (rac-2-[4-[1-Hydroxy-4-[4-(hydroxydiphenylmethyl) piperidin-1-yl]butyl]phenyl]-2-methylpropionic acid hydrochloride; Allegra) and desloratadine (8-Chloro-6,11-dihydro-11-(4-piperidylidene)-5H-benzo[5,6]cyclohepta[1,2-b]pyridine; Clarinex ). Lowering the pH from 7.4 to 5.8 decreased the affinity of [3H]mepyramine for histamine H1 receptors from 1.7 to 7.5 nM while the opposite was observed with [3H]levocetirizine, whose affinity increased from 4.1 to 1.5 nM. Competition curves with [3H]mepyramine indicated that decreasing the pH from 7.4 to 5.8 led to a 2- to 5-fold increase in the affinity of fexofenadine and levocetirizine, no change in affinity for desloratadine and a 5- to 10-fold decrease in affinity for mepyramine and histamine. Kinetic experiments showed that the increase in affinity of levocetirizine and, to a lesser extent, fexofenadine were totally attributable to a lower dissociation rate at acidic pH (t1/2 increasing from 77 to 266 min and from 71 to 135 min, respectively). Although the affinity of desloratadine remained unchanged, lowering the pH caused a decrease in its dissociation rate (t1/2 of 50 and 256 min at pH 7.5 and 5.8, respectively)…
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