Stereoselective pharmacokinetics and pharmacodynamics of organic nitrates in rats

Plasma concentration and vasodilating effect after i.v. bolus injection of stereoisomeric organic nitrates were evaluated. Pharmacokinetics of mononitrates was analyzed with a linear one-compartment model. The apparent volumes of distribution were almost identical, but systemic clearances were different among stereoisomers. The concentration data after dinitrate administration could be described based on a two-compartment model with elimination only from the central compartment via metabolism to mononitrate, and then mononitrate-dependent metabolic clearance was estimated. In the vasodilation by mononitrate administered intravenously, the maximum effect was not observed. The reduction of mean arterial pressure from baseline level was related to plasma concentration with a log-linear model. The pharmacological effect following dinitrate dosing was analyzed by a sigmoidal Emax model assuming a simple additive effect of dinitrate and mononitrate. Although almost the same Hill's constant and maximum effect (Emax) values were estimated, the concentrations required to produce 50% of Emax (EC50) differed among stereoisomers. The clearance and EC50 values of stereoisomers with nitrate group at the exo position were generally higher than those with the same group at the endo position. This suggests that the stereostructure of organic nitrates controls the vasodilator potency and duration of action.