Pharmacokinetic determinants of nitrate action.

An update on some of the recent studies relating to organic nitrate pharmacokinetics and pharmacodynamics is presented. The systemic clearance of nitroglycerin was found to be unaffected by portacaval shunting in animals. Thus, the liver only plays a minor role in the metabolism of systemic nitroglycerin. Organic nitrates are extensively taken up by blood vessels in which metabolic activation can occur to produce vascular activity. During sustained therapy, nitrate metabolites may decrease the systemic and hepatic clearance of the parent drug, thus increasing its plasma concentration. Metabolites could also decrease the extent of metabolism in vascular tissues, thus contributing to vascular nitrate tolerance. Therefore, during long-term angina therapy when metabolites are present, the same plasma nitrate concentration may produce less effects compared with that obtained after acute dosing. Nitrate action was shown to be possibly dependent on the rate of drug input. An alternate dosing mode is proposed that speculatively may provide an improvement in producing and maintaining nitrate action in long-term angina therapy.