Plasma profile and haemodynamic tolerance to isosorbide-5-mononitrate in controlled-release form.
1. Plasma concentrations and some haemodynamic parameters known to be affected by nitrates, were monitored in healthy volunteers who received three different dose regimens of isosorbide-5-mononitrate (5-ISMN) over 5 day study periods. 2. No haemodynamic tolerance was found in the 60 mg once-daily dose schedule which produced high plasma concentrations during the daytime but concentrations no greater than 100 ng ml-1 at night. In contrast, a dose regimen of 60 mg followed by 30 mg 12 h later and thereafter every 8 h until the fifth day induced complete haemodynamic tolerance. With this dose regimen the minimum plasma concentrations were never below 300 ng ml-1. A significant attenuation of haemodynamic effects was also found with the third dose regimen, 60 mg followed by 30 mg 6 h later for 5 days, which produced minimum plasma concentrations of between 100 ng ml-1 to 300 ng ml-1; the degree of attenuation rose as trough plasma concentrations increased. 3. In conclusion, 60 mg 5-ISMN in a controlled-release (Durules) preparation given once daily was the only dose regimen not inducing nitrate tolerance.
Jähnchen
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Division of Clinical Pharmacology, Benedikt Kreutz Rehabilitationszentrum, Bad Krozingen, Germany.
D000328:Adult; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D004361:Drug Tolerance; D006207:Half-Life; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D007548:Isosorbide Dinitrate / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D008297:Male; D014665:Vasodilator Agents / Q000008:administration & dosage / Q000097:blood*
D003692:Delayed-Action Preparations; D014665:Vasodilator Agents; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate