Plasma Level Of Isosorbide Dinitrate Research Articles

トリバレリル化β‐シクロデキストリン膜を用いた水溶性薬物の放出制御

Among various acylated β-cyclodextrins where all hydroxyl groups are substituted with different acyl groups, trivaIeryl β-cyclodextrin (TV-β-CyD) preferentially formed a transparent, adhesive thin-film. For example, when ethanol solution of TV-β-CyD was spread on the backing membranes such as polyethylene terephthalate film, polyethylene film and aluminium foil, a transparent film was formed, the film being tightly stuck on the membranes. The detaching force of TV-β-CyD film was higher and the decrease in the force by the addition of oleic acid was smaller than those of a commercial silicone pressure-sensitive adhesive which is used in transdermal drug delivery system. A vasodilator, isosorbide dinitrate (ISDN), was incorporated in TV-β-CyD film in molar ratios of 1 : 1 and 2 : 1 (ISDN : TV-β-CyD). The release rate of ISDN from TV-β-CyD film increased with increase in the film area, and slightly increased by the addition of oleic acid in the film. The plasma levels of ISDN after topical application of TV-β-CyD film containing ISDN to abdominal skin of rats were maintained 100 ng/ml for about 10 hours. The results suggests that TV-β-CyD film can serve as a drug reservoir for prolonged release of water-soluble drugs in transdermal preparations.

Transmucosal controlled systemic delivery of isosorbide dinitrate: in vivo/in vitro correlation

A bilayer track field-shaped transmucosal therapeutic system (TmTs) has been developed for the systemic delivery of therapeutic agents that are subject to an extensive pre-systemic clearance, using isosorbide dinitrate (ISDN) as the model drug. The transmucosal systemic delivery of ISDN was investigated by single gingival application of TmTs to beagle dogs. The cumulative absorption profiles and pharmacokinetic profiles of ISDN were monitored. Both were found to be directly correlated with the release profiles of ISDN determined by in vitro dissolution studies. An excellent (1:1) correlation at Level A was achieved when the dissolution test was conducted in a medium of pH 6.8 with the paddle rotating at a rotation speed of 200revs./min. Furthermore, the transmucosal systemic delivery of ISDN from TmTs was observed to depend on the release rate of ISDN: as the release rate decreased, the plasma level of ISDN was prolonged, but with no reduction in bioavailability. The systemic bioavailability of ISDN following transmucosal delivery through the oral mucosae can be modulated by controlling the ratio of ISDN loading in the fast- and sustained-release layers (F/S) as well as ISDN content in sustained-release layer. The effect was demonstrated in both in vitro and in vivo studies, which attained an vitro/in vivo correlation of 1:1. The excellent correlation achieved suggests that the in vivo performance of the TmTs formulation can be accurately predicted from the in vitro release profiles.

Influence of emotional stress on pharmacokinetics of isosorbide dinitrate intraperitoneally administered to rats.

The plasma level of isosorbide dinitrate intraperitoneally administered to rats stressed by foot-shock was almost the same as that in non-stressed control rats. However, levels of its metabolites, 5-isosorbide mononitrate and 2-isosorbide mononitrate, were lower in stressed rats than in non-stressed rats, suggesting that stress may influence the metabolism and/or excretion of the metabolites.

Antiischemic effects of a newly developed capsule containing 120 mg isosorbide dinitrate in sustained release form

It is well established that constant nitrate plasma levels, as generated by “q 8 hrs” ingestions as well as by transdermal applications, induce an attenuation or even complete loss of the antiischemic effects during chronic treatment due to the development of tolerance.1–3 As we have shown first in 1983, the once-daily ingestion of isosorbide dinitrate with its waxing and waning plasma levels prevents the development of tolerance during chronic treatment.1,2 However, the duration of action of that intermittent dosage regimen was rather limited and inconsistent. To extend the duration of the antiischemic effects of a once-daily dosage, a new formulation, i.e., a capsule containing 120 mg of isosorbide dinitrate in slow release form, was created. This study assessed this newly developed capsule with regard to the antiischemic effects at 2 hours, 6 hours and 12 hours after its ingestion. Additionally, the plasma levels of isosorbide dinitrate and its active metabolites isosorbide-2-mononitrate and isosorbide-5-mononitrate were determined.

Isosorbide dinitrate in plasma and dialysate during haemodialysis.

In 10 patients with end stage renal disease on regular haemodialysis the plasma concentrations and dialyzer clearance of isosorbide dinitrate (ISDN) were determined after an oral dose of a retarded release formulation of 60 mg ISDN. The maximal plasma concentration of ISDN 2-7 h after oral administration was higher (14 ng/ml) than has been reported in healthy volunteers. The haemodialyzer clearance of ISDN was 92.4 ml/min at a blood flow of 200 ml/min and dialysate flow of 500 ml/min. During a 5-h haemodialysis an average of 0.3 mg ISDN was removed from the patient's circulation, representing about 0.5% of the administered dose and about 3% of the available drug in the circulation. No influence of haemodialysis on the plasma level of ISDN was found.

Pharmacokinetics of intravenous isosorbide-dinitrate.

The kinetics of isosorbide dinitrate (ISDN) after i.v. administration and the absolute availability of an oral slow release preparation (SR) were studied in young healthy volunteers. ISDN and the 2- and 5-mononitrates of isosorbide (2-MN, 5-MN) were determined by GLC. After i.v. administration plasma levels of ISDN declined biexponentially and could be adequately described by an open two compartment body model. Distribution half-life was extremely rapid (2-5 min). Terminal disappearance had a half-life of 67 (62-75) min (mean, range). Total plasma clearance was 1.6 (1.2-2.2) litres X min-1, thus approaching liver blood flow. Nevertheless, absolute systemic availability (F) or oral ISDN amounted to 22% (16-29%). Assuming that oral ISDN is completely absorbed and blood levels do not exceed serum levels, an upper limit of hepatic clearance (liver blood flow 1.5 litres X min-1 X (1-F/100)) can be estimated, which is significantly smaller (p less than 0.05) than the measured clearance. This finding is best interpreted by assuming that ISDN is partly eliminated by extrahepatic routes, which is further substantiated by a different pattern of metabolites after i.v. and oral dosing. Whereas after i.v. administration more 2-MN is produced, 5-MN is the main metabolite after oral ISDN. Since the glutathione-S-transferases are found in the cytosol of most cells, it seems likely that other organs than the liver contribute to the metabolism of ISDN.