Due to complex pharmacokinetics and rapid tolerance development, future studies on nitrate tolerance should utilize homogenous patient groups and nitrates with very short half-lives.
Rapid tolerance and PK variability limit repeated nitrate dosing; leaves open refined regimens for homogeneous short-acting nitrate trials.
There is strong evidence that nitrate tolerance develops rapidly during repeated administration in the systemic resistance vascular bed and that there exists cross tolerance between different nitrates. There are divergent opinions on how tolerance in the systemic capacitance and the pulmonary vascular bed develops. This may be explained by real differences in tolerance development in ischemic heart disease and congestive heart failure but also by the use of several different preparations of nitrates in the studies performed. Available data on the pharmacokinetics of nitrates present a complex picture with highly variable bioavailability, clearance and apparent volume of distribution both inter‐ and intraindividually. It is suggested that nitrate tolerance should be studied in very homogenous groups of patients with well defined hemodynamics. The nitrate used should have a very short half‐life allowing for simulation of various modes of administration by intravenous infusion.
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Björn Beennann (1986) studied this question.
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