Kinetics of isosorbide dinitrate and relationships to pharmacological effects

1 The inter-relationships among oral isosorbide dinitrate (ISDN) dose, drug pharmacokinetics and pharmacological effects were studied in 12 angina patients following single and chronic doses of 15, 30, 60 and 120 mg. 2 Significant accumulation of intact ISDN in plasma was observed after four times a day dosing at 30, 60 and 120 mg for 1 week. 3 The area under the plasma concentration v time curve (AUC), form 0-6 h, was shown to be proportional to dose following single doses. In contrast, AUC increased disproportionately to dose after chronic dosing. 4 Pharmacokinetic correction provided modest improvements in the dose-response relationships of ISDN. 5 Adverse hypotensive effects were observed in five patients after the single 60 mg dose. These patients showed statistically higher AUC and lower intrinsic clearance of ISDN at doses of 15, 30 and 60 mg compared to those who did not develop adverse effects. A possible relationship exists, therefore, between lower drug clearance and hypersensitivity to ISDN.