Role of the liver in the disposition of intravenous nitroglycerin in the rat

Abstract

Previous studies have indicated that the liver is the main site of nitroglycerin (NTG) elimination when the drug is systematically infused. To examine this hypothesis, we measured the apparent systemic clearance (Cl s) of nitroglycerin in anesthesized rats receiving a constant intravenous infusion at a dose of 100 μg per kg per min. Animals were divided into shunt and sham groups; the former had undergone a portal vein ligation 10 days prior to the study, while the latter was subjected to a sham operation. On the study day, half of the animals of each group also received probenecid at 200 mg/kg, i.v., a drug previously reported to inhibit organic nitrate ester reductase (ONER) activity in rat liver. Arterial NTG samples were obtained at 41, 43 and 45 min of infusion in all four experimental groups; Cl s was 439 ± 32 ml per kg per min ( x ± S.E. ) in sham, 460 ± 44 in sham and probenecid, 477 ± 39 in shunt, and 461 ± 34 in shunt and probenecid animals. During NTG infusion, hepatic blood flow (measured with a constant infusion of indocyanine green) was decreased markedly in shunted rats as was liver/body weight, indicating hepatic atrophy. The specific activity of hepatic ONER was similar in all four groups. In spite of marked differences in hepatic blood flow and hepatic mass, the Cl s was similar in all four groups. The liver does not appear to be a major site for the elimination of systemic nitroglycerin as hitherto assumed.