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.