Pharmacokinetics of isosorbide dinitrate after intravenous infusion in human subjects

Plasma concentrations of isosorbide dinitrate have been measured after intravenous infusion of drug at a rate of 5.0 mg h-1 for 150 min and after single equal oral doses of 12.5 mg of drug in solution to two normal human subjects. During the infusion, uneven plateau concentrations were approached after 30 min. The calculated average steady-state plasma levels were 258 ng ml-1 and 514 ng ml-1 in the two subjects respectively. The half-life of elimination of isosorbide dinitrate after termination of the infusion was 9--10 min. After oral doses, peak plasma levels of 26.6 ng ml-1 and 12.7 ng ml-1 occurred at 10 min and 20 min in the two subjects respectively. The terminal half-life of drug after the oral doses was much longer than the elimination half-life (about 10 min), and was associated with the absorption phase. Fairly good agreement was obtained between the observed concentrations and those predicted by a one-compartment open model. The systemic availability of isosorbide dinitrate after the oral doses was up to only 3 per cent of the equal doses infused, indicating that presystemic elimination processes accounted for very large proportions of the oral doses. The systemic clearances of drug after infusion of 0.32 l min-1 and 0.16 l min-1 were unexpectedly low for a drug of reported high liver extraction ratio.