ORGANIC NITRATES: RELATIONSHIP BETWEEN BIOTRANSFORMATION AND RATIONAL ANGINA PECTORIS THERAPY

Abstract

Unchanged organic nitrates have a very transient lifetime in blood after jugular vein administration. The nitrate metabolites circulate for hours after the transient vascular response and are eventually cleared into the urine by the kidney. High doses of various organic nitrates are quite potent when administered via the jugular vein but are inactive as vasodepressors when injected into the portal vein. After portal injection of radio active organic nitrates, little or none of the intact molecule reaches the circulation but rapid liver denitration is indicated by the appearance of high blood levels of metabolites which are incapable of producing a vasodepression. Similarly, when organic nitrates are administered orally and hence go via the portal vein directly to the liver, they are de graded rapidly and little if any of the parent compound is available in the circulation to relax vascular smooth muscle. The biotransformations in rats are catalyzed rapidly by the liver enzyme glutathione-organic nitrate reductase. Human liven biopsy samples have the same enzyme capacity for denitration as the rat liver. These results lead to the conclusion that there is no rational basis for the use of "long-acting" nitrates (administered orally) in the prophylactic therapy of angina pectonis.