Clinical pharmacokinetics and pharmacodynamics of glyceryl trinitrate and its metabolites

This review discusses the pharmacokinetics and pharmacodynamics of glyceryl trinitrate (nitroglycerin; GTN) pertinent to clinical medicine. The pharmacokinetics of GTN associated with various dose regimens are characterised by prominent intra- and inter-individual variability. It is, nevertheless, important to clearly understand the pharmacokinetics and characteristics of GTN to optimise its use in clinical practice and, in particular, to obviate the development of tolerance. Measurements of plasma concentrations of GTN and of 1,2-glyceryl dinitrate (1,2-GDN), 1,3-glyceryl dinitrate (1,3-GDN), 1-glyceryl mononitrate (1-GMN), and 2-glyceryl mononitrate (2-GMN), its four main metabolites, remain difficult and require meticulous techniques to obtain reliable results. Since GDNs have an effect on haemodynamic function, pharmacokinetic analyses that include the parent drug as well as the metabolites are important. Although the precise mechanisms of GTN metabolism have not been elucidated, two main pathways have been proposed for its biotransformation. The first is a mechanism-based biotransformation pathway that produces nitric oxide (NO) and contributes directly to vasodilation. The second is a clearance-based biotransformation or detoxification pathway that produces inorganic nitrite anions (NO2-). NO2- has no apparent cardiovascular effect and is not converted to NO in pharmacologically relevant concentrations in vivo. In addition, several non-enzymatic and enzymatic systems are capable of metabolising GTN. This complex metabolism complicates considerably the evaluation of the pharmacokinetics and pharmacodynamics of GTN. Regardless of the route of administration, concentrations of the metabolites exceed those of the parent compound by several orders of magnitude. During continuous steady-state delivery of GTN, for instance by a patch, concentrations of 1,2-GDN are consistently 2-7 times higher than those of 1,3-GDN, and concentrations of 2-GMN are 4-8 times higher than those of 1-GMN. Concentrations of GDNs are approximately 10 times higher, and of GMNs approximately 100 times higher, than those of GTN during sustained administration. The development of tolerance is closely related to the metabolism of GTN, and can be broadly categorised as haemodynamic tolerance versus vascular tolerance. Efforts are warranted to circumvent the development of tolerance and facilitate the use of GTN in clinical practice. Although this remains to be accomplished, it is likely that, in the near future, regimens will be developed based on a full understanding of the pharmacokinetics and pharmacodynamics of GTN and its metabolites.