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Pharmacokinetics of Isosorbide Dinitrate in Healthy Volunteers After 24‐Hour Intravenous Infusion
Author(s) -
Bergami Alessandra,
Bernasconi Roberto,
Caccia Silvio,
Leopaldi Daniele,
Mizrahi Jacques,
Sardina Marco,
Urso Renato,
Warrington Steve J.,
Latini Roberto
Publication year - 1997
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/j.1552-4604.1997.tb05631.x
Subject(s) - isosorbide dinitrate , pharmacokinetics , anesthesia , intravenous infusions , medicine , clearance , heart rate , plasma concentration , chemistry , pharmacology , blood pressure , urology
No studies have examined the pharmacokinetics of isosorbide dinitrate (ISDN) after infusion of long duration, even though such infusions are used in patients. We therefore measured ISDN and its active metabolites, isosorbide‐5‐mononitrate (IS5MN) and isosorbide‐2‐mononitrate (IS2MN), in plasma of 9 healthy volunteers who received a continuous intravenous infusion of ISDN for 24 hours at a dose rate that lowered diastolic blood pressure by 10% during the first 30 minutes of infusion. All subjects tolerated the infusion except one who experienced intolerable headache. Five subjects received 1 μg · min −1 · kg −1 , one 2 μg · min −1 · kg −1 , and two 4 μg · min −1 · kg −1 ISDN, whereas the full rate of 6 μg · min −1 · kg −1 was used continuously in one subject. At all infusion rates the plasma concentrations of ISDN were higher at 24 hours than at earlier times, suggesting that a steady‐state condition had not been reached at that time. The same was true for the mononitrate metabolites, which reached higher plasma concentrations and were cleared more slowly than the parent compound after the end of the infusion. Apparent elimination half‐lives of ISDN, IS2MN, and IS5MN were 67 ± 10 minutes, 115 ± 13 minutes, and 272 ± 38 minutes, respectively. Comparison of low‐rate infusions (1 and 2 μg · min −1 · kg −1 ) with high‐rate infusions (4 and 6 μg · min −1 · kg −1 ) showed that the plasma concentration ratios at 24 hours of mononitrate metabolites to parent drug and apparent plasma clearance of ISDN were almost halved at the higher infusion rates.