Effects of competitive red blood cell binding and reduced hematocrit on the blood and plasma levels of [14C]Indapamide in the rat.
The effects of chlorthalidone and acetazolamide on the red blood cell binding of indapamide were investigated. Both drugs caused a substantial decrease in the amount of indapamide bound to the erythrocytes in vitro. This effect was demonstrated by a change in the indapamide blood/plasma ratio from approximately 6 in control samples, to a value of 1 when either of the displacing agents was added. Coadministration of acetazolamide with 14C-labeled indapamide to rats, resulted in a 5-fold drop in the blood levels of total radioactivity, relative to rats dosed with [14C]indapamide alone. Concomitantly, there was a 2-fold increase in the plasma levels of total radioactivity after acetazolamide coadministration. In rats whose hematocrits had been reduced by extensive bleeding, there were only minor alterations in the blood/plasma partitioning of [14C]indapamide. Thus, chlorthalidone and acetazolamide were able to displace indapamide from erythrocytes in vitro and in vivo, possibly by competition at a carbonic anhydrase binding site. The pharmacokinetics of drugs which are extensively bound to erythrocytes may be significantly altered by the presence of other agents capable of competitive binding.
D000086:Acetazolamide / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D002250:Carbon Radioisotopes; D002752:Chlorthalidone / Q000494:pharmacology; D004232:Diuretics / Q000097:blood*; D004912:Erythrocytes / Q000378:metabolism*; D006400:Hematocrit; D007190:Indapamide / Q000097:blood* / Q000378:metabolism; D008297:Male; D051381:Rats; D011919:Rats, Inbred Strains
D002250:Carbon Radioisotopes; D004232:Diuretics; D007190:Indapamide; D000086:Acetazolamide; D002752:Chlorthalidone