Oral administration of clotrimazole and blockade of human erythrocyte Ca(++)-activated K+ channel: the imidazole ring is not required for inhibitory activity.

The Ca(++)-activated K+ (Gardos) channel of erythrocytes plays a crucial role in K+ loss and dehydration of sickle erythrocytes; a potential therapeutic strategy would be to prevent dehydration by specifically blocking this channel. The authors report here on the activity of the clotrimazole (CLT) metabolite, 2-chlorophenyl-bis-phenyl-methanol, which accounts for a portion of the blockade of the erythrocyte Gardos channel when CLT is given orally to normal volunteers. Administration of a single oral dose of 1 g of CLT to four normal healthy volunteers (approximately 15 mg/kg of body weight) resulted in 51% to 92% peak inhibition of the Gardos channel measured in whole blood 2 to 4 hr later. Inhibition remained detectable for 24 to 34 hr. Inhibition of the Gardos channel correlated best with the summed levels of CLT plus its two major metabolites (P < .002; apparent IC50 = 0.65 +/- 0.19 microM). In vitro experiments with 2-chlorophenyl-bis-phenyl-methanol revealed dose-dependent inhibition of K transport and displacement of specifically bound 125I-charybdotoxin. Thus, the imidazole ring of CLT, which is required for antimycotic activity and associated with most of the historically observed toxicity, is not necessary for inhibition of the Gardos channel.