Cardiac output is an apparent determinant of nitroglycerin pharmacokinetics in rats

The steady-state pharmacokinetics of nitroglycerin (NTG) were investigated in 11 rats after sequential infusions of either NTG alone (10 micrograms/kg/min) or NTG plus vasopressin (the latter at 5.5 mU/kg/min). Arterial and venous plasma concentrations of NTG in the femoral bed were obtained at 41 and 45 min during each infusion phase. Cardiac output was estimated twice in each animal using 85Sr and 141Ce microspheres. NTG systemic clearance in arterial plasma was found to be strongly correlated with cardiac output (r = 0.784, n = 22, P less than .001). Because NTG distribution between red blood cells and plasma was independent of concentration (up to 150 ng/ml in plasma) and hematocrit (25-48%), the systemic clearance of NTG in arterial blood could be estimated as about 3/4 of cardiac output. Vasopressin co-infusion decreased both the cardiac output and the arterial NTG plasma clearance, but it also increased the arteriovenous extraction of NTG. Thus, vasopressin had not net effect on the venous plasma clearance, of NTG. In animals with NTG infusions alone, cardiac output also significantly correlated with NTG venous plasma clearance (P less than .01) and arteriovenous extraction (P less than .05). These data indicate that, in the absence of vasopressin, NTG pharmacokinetics are dependent on the cardiac output, thus providing an example wherein the systemic clearance of a drug was shown to be related to systemic blood flow. These results support the concept that the vasculature acts as a clearing organ for organic nitrates, and they also provide a hemodynamic explanation for the high variability in NTG plasma concentrations observed under presumed steady-state conditions.