Block of HERG Potassium Channels by the Antihistamine Astemizole and its Metabolites Desmethylastemizole and Norastemizole

Abstract

Desmethylastemizole and astemizole cause equipotent block of HERG channels, and these are among the most potent HERG channel antagonists yet studied. Because desmethylastemizole becomes the dominant compound in serum, these findings support the postulate that it becomes the principal cause of long QT syndrome observed in patients following astemizole ingestion. Norastemizole block of HERG channels is weaker; thus, the risk of producing ventricular arrhythmias may be lower. These findings underscore the potential roles of some H1-receptor antagonist metabolites as K+ channel antagonists.

Silencing the Activity and Proliferative Properties of the Human EagI Potassium Channel by RNA Interference

“…Imipramine blocks many cardiac and neuronal sodium, calcium, and potassium channels as well as EGL2-channels, whereas astemizole is the paradigmatic inhibitor of HERG channels (15). Unfortunately, there is a broad co-expression of these other channels with EagI in both naturally expressing cell lines and cancer tissues (data not shown) and the expected, severe therapeutic side effects associated with use of these drugs have been reported (32). Moreover, the need for a specific blocker of EagI stems not only from a possible therapeutic use but also from the difficulties in clarifying both the physiological role of the channel in brain cells and its pathophysiological relevance in tumor cells.…”

ICH E14 Q&A(R2) document: commentary on the further updated recommendations on thorough QT studies

“…Astemizole, now withdrawn from the market, is a typical example [6,7]. A more recent example is dextropropoxyphene for which the metabolite concentrations are 3-5.5 times greater than the parent drug and both are active at hERG channels [8].…”

The Binding Site for Channel Blockers That Rescue Misprocessed Human Long QT Syndrome Type 2 ether-a-gogo-related Gene (HERG) Mutations

“…In humans it undergoes oxidative N-alkylation generating norastemizole (Fig. 4) reported to have a reduced IC 50 of 27.7 nM with about 50% of HERG current resistant to block by norastemizole (28). This observation suggests that hydrophobic side chains attached to tertiary amines in noncardiac HERG-blocking antihistamines are important for block (29).…”

“…The HERG channel blockers we have used block the open state (23,24,28) indicating that pharmacological rescue of HERG G601S was mediated by the binding of these blockers to a receptor site in the hydrophobic inner vestibule of HERG soon after assembly of channel tetramers. This interpretation was supported further by our observation that rescue was reduced strongly when the pore residue HERG Phe-656 was mutated into a more hydrophilic cysteine and by our experiments with astemizole/norastemizole in which a hydrophobic substituent to the basic nitrogen of these molecules was identified as crucial for both rescue and block.…”