[Pharmacokinetics of isosorbide dinitrate studied by the extrapolation model].
To make a pharmacokinetic model of isosorbide dinitrate (ISDN), we infused ISDN at 1, 10 or 30 micrograms.kg-1.min-1 into anesthetized rabbits and measured concentrations of ISDN and its metabolites (2-ISMN and 5-ISMN) in plasma, urine and bile. We found the concentration gradient of ISDN between arteries and veins and between the ascending aorta and femoral artery. These concentration gradients may occur due to metabolism and accumulation of ISDN in many organs and tissues, let alone the vascular endothelium. There was no significant difference in plasma concentrations of ISDN or its metabolites between the hepatic vein and femoral vein. It seems that ISDN is metabolized in various organs and tissues. By ISDN infusion of more than 10 micrograms.kg-1.min-1, the plasma concentration of ISDN showed a pronounced increase. It appears that there is metabolic saturation of ISDN. Using these informations, we extrapolated the model to human and the estimated values were compared with observed values to determine the validity of the extrapolation model. There was no remarkable differences between the estimated values and observed values. This suggests the validity of the model. The plasma concentrations of ISDN, estimated by this extrapolated model, showed a linear increase (Y = 30X) with the flow rate range of 0.2-5.0 micrograms.kg-1.min-1, when the metabolic rate was normal. With ISDN infusion of more than 5.0 micrograms.kg-1.min-1, the plasma concentrations of ISDN showed a pronounced increase. In the conditions of impaired metabolism, the plasma concentrations of ISDN increase exponentially.(ABSTRACT TRUNCATED AT 250 WORDS)
Matsumoto
J
J
Department of Anesthesiology, Akita University School of Medicine.
Ohtaka
K
K
Enzan
K
K
Koizumi
A
A
Suzuki
M
M
D000818:Animals; D006801:Humans; D007548:Isosorbide Dinitrate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D008297:Male; D008954:Models, Biological; D011817:Rabbits
D007548:Isosorbide Dinitrate