Abstract

The rate of degradation of several organic nitrates by isolated perfused rat liver was compared to the rates of metabolism in vivo. The disappearance of erythrityl tetranitrate (T_1/2, one minute) indicated essentially complete removal in each pass through the liver. The half times of glyceryl trinitrate (two minutes), isosorbide dinitrate (five minutes) and pentaerythritol trinitrate (seven minutes) were longer. The observed in vivo half times of isosorbide dinitrate and glyceryl trinitrate were one minute each whereas the half-time of mannitol hexanitrate was approximately 10 seconds. The disappearance of parent compound correlated with a rapid rise in blood levels of metabolites. Rat blood in vitro metabolized mannitol hexanitrate rapidly (T_1/2, one mintue), but glyceryl trinitrate and isosorbide dinitrate were metabolized much more slowly (T_1/2, 15-20 minutes). It is concluded that the rapid in vivo disappearance of organic nitrates represents the sum of distribution, nonhepatic metabolism (mannitol hexanitrate) and hepatic metabolism which is limited only by the rate at which the drug is presented to the liver via the blood.