Isosorbide 5‐mononitrate pharmacokinetics in humans

Abstract

When isosorbide 5-mononitrate was intravenously infused at a rate of 4 mg h-1 for 2.5 h to five human subjects, its concentrations in plasma increased slowly to 185 ng ml-1 +/- 5 per cent C.V. at 2.5 h and a steady-state plasma level was not reached during the infusion. When the infusion was discontinued, plasma drug concentrations declined with an elimination half-life of 4.2 h +/- 6 per cent C.V. The systemic clearance after the infusion doses was 132 ml min-1 +/- 18 per cent C.V. and the volume of distribution was 48.4 +/- 16 per cent C.V. After equal oral doses of 10 mg, the peak plasma isosorbide 5-mononitrate concentration of 191 ng ml-1 +/- 16 per cent C.V. was reached at 1.1 h +/- 30 per cent C.V., and plasma levels declined with a terminal half-life of 4.9 h. The complete systemic availability of isosorbide 5-mononitrate indicated that pre-systemic elimination after the oral doses was negligible. A one-compartment open model appeared adequate to describe the plasma level data after intravenous infusion and oral dose. After single oral doses of 10 mg isosorbide dinitrate, the peak plasma concentration of the 5-mononitrate metabolite of 72 ng ml-1 +/- 27 per cent C. V. occurred at 1.7 h +/- 41 per cent C.V. Approximately 50 per cent (range 22--68 per cent) of the oral dose of isosorbide dinitrate circulated in plasma as the 5-mononitrate metabolite. The pharmacokinetics of isosorbide mononitrates are markedly different to those of the parent dinitrate and these differences follow from the greater systemic availability and volume of distribution of the mononitrates.

The effect of food on the oral absorption of isosorbide‐5‐mononitrate.

“…The effect of food on the oral absorption of isosorbide-5-mononitrate While complete gastrointestinal absorption of isosorbide-5-mononitrate (IS-S-MN) has been shown in fasting subjects (Taylor et al, 1981; Abshagen et al, 1981), nothing is known about the influence of concomitant food intake on the pharmacokinetics of this drug. We measured plasma drug concentrations after a single oral dose of IS-S-MN in healthy human subjects, both fasting and after a standard breakfast.…”

Isosorbide 5-Mononitrate Pharmacokinetics

“…Two earlier reports [4,16] of the pharma cokinetics of isosorbide 5-mononitrate have been complemented and extended by a more recent study involving a group of 12 healthy male volunteer subjects who received 20 mg of isosorbide 5-mononitrate orally as stan dard tablets or by intravenous infusion at a rate of 8 mg/h [17], During intravenous infu sion, mean plasma drug concentrations slowly reached 351 ± (SD) 41 ng/ml at the end of the infusion period of 2.5 h (fig. 3).…”

“…2) [2,3]. Af ter absorption of an oral dose of isosorbide dinitrate from the gastrointestinal tract, ex tensive initial (first-pass) metabolism in the liver (and other tissues) converts about 50% of the dose to isosorbide 5-mononitrate, about 20% to isosorbide 2-mononitrate and about 25% escapes metabolism to reach the systemic circulation as the unchanged drug (4)(5)(6)(7), Studies in animals [8. 9] and in humans [10,11] have shown that the mononitrate metabolites share the pharmacological activ ity of the parent isosorbide dinitrate, al though they are probably intrinsically less potent.…”

Isosorbide 5-Mononitrate in the Treatment of Left Ventricular Failure following Acute Myocardial Infarction

“…Certainly previous data re garding isosorbide dinitrate have been en couraging [5]. Isosorbide mononitrate, how ever, has certain theoretical advantages over the dinitrate [6,7] and we therefore designed a study to explore the potential of isosorbide 5-mononitrate for the treatment of acute left ventricular failure in myocardial infarction. Since this was essentially a preliminary study we adopted an open protocol involving both intravenous and oral phases spanning a 48-hour period.…”