title: Oral administration of clotrimazole and blockade of human erythrocyte Ca(++)-activated K+ channel: the imidazole ring is not required for inhibitory activity.
abstract: 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.
authors.affiliation: Department of Pathology, Children's Hospital, Boston, Massachusetts, USA.
authors.forename: C
authors.initials: C
authors.lastname: Brugnara
authors.forename: C C
authors.initials: CC
authors.lastname: Armsby
authors.forename: M
authors.initials: M
authors.lastname: Sakamoto
authors.forename: N
authors.initials: N
authors.lastname: Rifai
authors.forename: S L
authors.initials: SL
authors.lastname: Alper
authors.forename: O
authors.initials: O
authors.lastname: Platt
mesh_terms: D000284:Administration, Oral; D000328:Adult; D002118:Calcium / Q000502:physiology*; D003022:Clotrimazole / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D004912:Erythrocytes / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D011188:Potassium / Q000378:metabolism; D026902:Potassium Channel Blockers; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D026902:Potassium Channel Blockers; D003022:Clotrimazole; D011188:Potassium; D002118:Calcium