Blood vessel uptake and metabolism of organic nitrates in the rat

Abstract

Recent reports have suggested that the unusual pharmacokinetics observed for nitroglycerin (NTG) and isosorbide dinitrate (ISDN) may be partially explained by extensive uptake and/or metabolism of these drugs by vascular and other extrahepatic tissues. Using the rat as an animal model, this hypothesis was examined by in vivo intravessel NTG and [14C]ISDN infusion and injection into various vessel segments, viz. the femoral vein, inferior vena cava [IVC: lower, middle and upper) and the aorta. NTG and [14C]ISDN concentrations were determined in these blood vessels and in plasma. Blood vessel segments nearest the input site had the greatest amounts of nitrate, whereas segments further away from the input site had progressively less nitrate, with the exception of aorta, which appeared to take up NTG less extensively, on a per weight of vessel basis, than the IVC. Blood vessel NTG concentrations (nanogram per gram) were generally higher (10-fold) and declined about twice as slowly as NTG plasma concentrations (nanograms per milliliter). [14C]NTG and [14C]ISDN were also incubated with cofactors in IVC, aorta, abdominal muscle, lung and liver. The amounts of nitrate metabolites formed from parent drug were larger in each extrahepatic tissue incubation than in the controls (P less than .05). The results are consistent with the hypothesis that vascular and other extrahepatic tissues can take up and/or metabolize organic nitrates. The data appear to provide a partial explanation for the large systemic clearance seen with nitrates and appear consistent with existing mechanistic hypotheses for the vascular action of these compounds.