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PubMed1983

Oral absorption and disposition of isosorbide dinitrate and isosorbide mononitrates in man.

The plasma concentrations of isosorbide dinitrate (ISDN) and its two pharmacologically active metabolites isosorbide 2-mononitrate (IS-2-MN) and isosorbide 5-mononitrate (IS-5-MN) were determined after oral administration of 20 mg ISDN and 20 mg of each of the mononitrates. The mean concentration-time curve of ISDN showed a peak of 51.6 ng/ml 15 min after drug intake, and declined bi-exponentially with a terminal half-life of 36.5 min. The mean concentrations of the simultaneously measured metabolic products IS-2-MN and IS-5-MN reached a maximum of 40.5 ng/ml and 144.4 ng/ml, respectively. In contrast, after the direct ingestion of isosorbide mononitrates, peaks of 409.1 ng/ml (IS-2-MN) and 483.2 ng/ml (IS-5-MN) were observed in the corresponding mean curves. Mean half-lives of 1.72 h for IS-2-MN and 4.20 h for IS-5-MN were calculated. The mean apparent volumes of distribution were 44.5 l (IS-2-MN) and 34.4 l (IS-5-MN), suggesting that the isosorbide mononitrates are distributed throughout the whole body fluid. After ISDN administration, it was estimated that 3.0 mg IS-2-MN and 7.8 mg IS-5-MN reached the systemic circulation. This corresponds to 63% of the ISDN dose being converted to isosorbide mononitrates by metabolic processes.

Administration, Oral↗
PubMed1983

Determination of isosorbide as a metabolite of isosorbide dinitrate in human urine by capillary gas chromatography with electron-capture detection.

A method for the determination of isosorbide as a metabolite of isosorbide dinitrate at concentrations down to 200 ng/ml in human urine is described. After addition of a known amount of isomannide as internal standard to 50 microliter of urine, both compounds are extracted at basic pH into chloroform-isopropanol (4:1, v/v), which is then evaporated to dryness. They are then derivatized with heptafluorobutyric anhydride, and isosorbide is quantitated by capillary gas chromatography with electron-capture detection. A conjugate of isosorbide is determined in urine after enzymatic hydrolysis.

Chromatography, Gas↗
PubMed2000

Response to changing plasma concentrations of isosorbide-bound NO2 during acute and sustained treatment with isosorbide dinitrate in patients with coronary artery disease.

BACKGROUND: The mechanisms behind development of tolerance to nitrate effects during sustained, asymmetric isosorbide dinitrate (ISDN) therapy are not fully understood. HYPOTHESIS: The study was undertaken to investigate the changes of the relationships between left ventricular (LV) function and plasma concentrations of ISDN and its vasoactive metabolites (2- and 5-ISMO) during acute and sustained, asymmetric ISDN therapy. METHODS: Left ventricular function and plasma concentrations of ISDN, 2- and 5-isosorbide mononitrates (P-ISDN, P-2- and 5-ISMO) were measured at rest and at supine exercise before and for 4 h after peroral 30 mg ISDN in 15 patients with coronary artery disease, all with initial exercise pulmonary artery wedge pressure (PAWP) > 25 mmHg. Seven patients were untreated (acute group), while eight received 30 mg ISDN b.i.d. for 2 weeks before the invasive study. P-ISDN and the concentration of available isosorbide-bound nitrate (NO2) in plasma (P-ISDN.2 + P-2-ISMO + P-5-ISMO) (P-NO2) were used as measures of the nitric oxide (NO) offer to the tissues. RESULTS: Throughout the study, after administration of medication, all plasma concentrations, in particular P-ISDN, were higher in the chronic than in the acute group. Peak P-ISDN was reached after 15 min in the chronic group and after 25 min in the acute group, while P-2- and 5-ISMO reached maximum only after 40 min in both groups. At rest, the full effect on PAWP was observed after 10 min in both groups, but at markedly higher levels of P-ISDN and P-NO2 in the chronic group. Afterward, no further changes in PAWP were observed. During exercise, 1 h after medication, PAWP and stroke index to PAWP ratio (SI/PAWP) were normal in both groups. Thereafter, at slowly declining P-NO2, PAWP rose and SI/PAWP declined toward the initial level in the chronic group, but remained unchanged in the acute group, in spite of higher P-NO2 and greater NO release in the former. CONCLUSIONS: Patients receiving sustained, asymmetric 30 mg ISDN b.i.d. dosing had the same immediate beneficial effects on LV function during exercise after a morning dose as did untreated patients. However, in spite of higher P-NO2 and higher rate of NO release during sustained treatment, the effects deteriorated gradually 2 to 3 h after medication. The changes in metabolism and/or distribution of isosorbide-bound NO2 may possibly be part of the tolerance induced by long-term treatment, even with asymmetric dosing.

Aged↗
PubMed1998

Randomised trial of high-dose isosorbide dinitrate plus low-dose furosemide versus high-dose furosemide plus low-dose isosorbide dinitrate in severe pulmonary oedema.

BACKGROUND: Nitrates and furosemide, commonly administered in the treatment of pulmonary oedema, have not been compared in a prospective clinical trial. We compared the efficacy and safety of these drugs in a randomised trial of patients with severe pulmonary oedema and oxygen saturation below 90%. METHODS: Patients presenting to mobile emergency units with signs of congestive heart failure were treated with oxygen 10 L/min, intravenous furosemide 40 mg, and morphine 3 mg bolus. 110 patients were randomly assigned either to group A, who received isosorbide dinitrate (3 mg bolus administered intravenously every 5 min; n=56) or to group B, who received furosemide (80 mg bolus administered intravenously every 15 min, as well as isosorbide dinitrate 1 mg/h, increased every 10 min by 1 mg/h; n=54). Six patients were withdrawn on the basis of chest radiography results. Treatment was continued until oxygen saturation was above 96% or mean arterial blood pressure had decreased by 30% or to below 90 mm Hg. The main endpoints were death, need for mechanical ventilation, and myocardial infarction. The analyses were by intention to treat. FINDINGS: Mechanical ventilation was required in seven (13%) of 52 group-A patients and 21 (40%) of 52 group-B patients (p=0.0041). Myocardial infarction occurred in nine (17%) and 19 (37%) patients, respectively (p=0.047). One patient in group A and three in group B died (p=0.61). One or more of these endpoints occurred in 13 (25%) and 24 (46%) patients, respectively (p=0.041). INTERPRETATION: High-dose isosorbide dinitrate, given as repeated intravenous boluses after low-dose intravenous furosemide, is safe and effective in controlling severe pulmonary oedema. This treatment regimen is more effective than high-dose furosemide with low-dose isosorbide nitrate in terms of need for mechanical ventilation and frequency of myocardial infarction.

Acute Disease↗
PubMed1983

Absorption and excretion of isosorbide dinitrate and isosorbide-2-mononitrate in dogs.

In a crossover design four male dogs were given orally or i.v. [14C]isosorbide dinitrate (ISDN) or [14C]isosorbide-2-mononitrate (2-ISMN) at a dose of 1 mg kg-1 (70-80 microCi). Virtually all of the oral dose was absorbed and all of the radioactivity was excreted in the urine. The profile of serum radioactivity was similar after all drug administrations. ISDN was rapidly denitrated, giving rise to isosorbide-5-mononitrate (5-ISMN) as a major metabolite, and 2-ISMN as a minor metabolite. The apparent elimination half-life from serum of 2-ISMN and 5-ISMN was 2-3 h. More than 50% of the serum radioactivity after [14C]2-ISMN was due to unchanged drug. The apparent volume of distribution of 2-ISMN averaged 8.3 litres. The results show that, in contrast to ISDN, administration of 2-ISMN resulted in relatively high unchanged drug levels in the serum; the disposition of radioactivity after [14C]ISMN was however similar to that after [14C]ISDN. The findings support the concept that the concentrations of ISDN, 2-ISMN and 5-ISMN in the blood are inversely related to the rates of denitration, and that the vascular activity of the nitrates of isosorbide relates to the rates of their dinitration.

Absorption↗
PubMed1988

Comparative pharmacokinetics of isosorbide nitrates after repeated doses of sustained release isosorbide dinitrate.

The plasma kinetics of isosorbide dinitrate (ISDN), isosorbide-5-nitrate (IS-5-N) and isosorbide-2-nitrate (IS-2-N) were investigated in 20 healthy male and female volunteers, after b.i.d. administration over 2 days of sustained release ISDN 20 mg and 40 mg capsules (Iso Mack Retard 20 mg and 40 mg) and of a 40 mg sustained release ISDN tablet as reference formulation. The means of the individual maximum ISDN concentrations during the complete 2-day treatment amounted to 10.4 ng/ml after the 40 mg capsule, 5.3 ng/ml after the 20 mg capsule and 5.3 ng/ml after the reference tablet. The corresponding figures of the metabolically generated IS-5-N were 355.5 ng/ml, 168.8 ng/ml and 161.5 ng/ml, respectively. The measured amounts of IS-5-N are expected to contribute to the overall antianginal effect of at least the 40 mg capsule. According to the b.i.d. schedule, ISDN and the two mononitrates accumulated in the plasma after all three tested formulations. However, during the treatment with the 20 mg and the 40 mg capsules, accumulation was practically completed at the second day, while it was found to be more extended during treatment with the reference product. In terms of areas under the curve, the mean bioavailability of the 40 mg sustained release capsule relative to the reference formulation was 198% with respect to ISDN, and 197% both with respect to IS-2-N and IS-5-N. On the other hand, perfect dose-linearity of all relevant pharmacokinetic parameters of all three measured isosorbide nitrates was observed for the 20 mg and the 40 mg dose of the capsule.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1982

Plasma concentrations of isosorbide dinitrate and mononitrates after acute and chronic oral administration of isosorbide dinitrate in man.

Isosorbide dinitrate (Cedocard) was given orally to patients in doses of either 5, 20 or 40 mg t.i.d. for 19 days, and the plasma concentrations of unchanged product and of its mononitrates were measured. While the concentration of isosorbide 2-mononitrate remained stable, the concentration of isosorbide dinitrate and of isosorbide 5-mononitrate in plasma increased gradually during the first days of administration. Decrease in presystemic or systemic clearance is probably responsible for this phenomenon.

Administration, Oral↗
PubMed1984

Differences in the nitrite ion formation and the toxicological findings between isosorbide dinitrate and isosorbide-5-mononitrate.

In the metabolism of isosorbide dinitrate (ISDN), fast denitration with the formation of nitrite ions and a mononitrate plays an important role. In contrast, the denitration of isosorbide-5-mononitrate (IS-5-MN) to isosorbide is very slow. Accordingly po administration of high doses of ISDN (92.5 and 236 mg/kg) in conscious dogs led to maximum nitrite concentrations in the blood of 0.9 and 3.3 mg/liter, respectively. In contrast, with equimolar doses of IS-5-MN (75 and 191 mg/kg) we were able to detect nitrite ions reliably only at the higher dose and this gave a maximum blood concentration of 0.4 mg/liter. The rise in nitrite ion concentration is followed by the formation of methemoglobin. As is known from the literature, there is a rise in the activity of alkaline phosphatase in the serum of rabbits in addition to methemoglobin formation following repeated administration of sodium nitrite. So we have specifically investigated whether this is also the case following ISDN and IS-5-MN administration. On po administration of 236 mg/kg ISDN/day to dogs, there was a continuous rise in alkaline phosphatase from about the 20th day onward which we did not observe after the equimolar dose of IS-5-MN (191 mg/kg). NaNO2, 35 mg/kg po, led to a comparable maximal rise in methemoglobin to that obtained with 236 mg/kg ISDN. Repeated po administration of 35 mg/kg NaNO2/day also caused a rise in alkaline phosphatase. It is concluded that the formation of nitrite ions from ISDN is the reason for the rise in methemoglobin and alkaline phosphatase. The lower formation of nitrite ions from IS-5-MN can also be of clinical importance, at least in certain cases.

Alkaline Phosphatase↗
PubMed2002

Isosorbide-based aspirin prodrugs. II. Hydrolysis kinetics of isosorbide diaspirinate.

Aspirin prodrugs have been intensively investigated in an effort to produce compounds with lower gastric toxicity, greater stability or enhanced percutaneous absorption, relative to aspirin. This report describes the hydrolysis kinetics and aspirin release characteristics of isosorbide diaspirinate (ISDA), the aspirin diester of isosorbide. ISDA underwent rapid hydrolysis when incubated in phosphate buffered human plasma solutions (pH 7.4) at 37 degrees C, producing appreciable quantities of aspirin. In 30% human plasma solution the half-life was 1.1 min and 61% aspirin was liberated relative to the initial ester concentration. The hydrolysis kinetics of ISDA were monitored in aqueous solution at 37 degrees C over the pH range 1.03-9.4. The aqueous hydrolysis followed pseudo-first-order kinetics over several half-lives at all pH values, resulting in a U-shaped pH rate profile. Salicylate esters and salicylic acid were formed during these processes. The hydrolysis characteristics of ISDA were also investigated in pH 7.4 phosphate buffered solutions containing alpha-chymotrypsin [EC 3.1.1.1] (t(1/2)=200.9 min), carboxyl esterase [EC 3.1.1.1] (t(1/2)=31.5 min), human serum albumin (t(1/2)=603 min), purified human serum butyrylcholinesterase [EC 3.1.1.8] (80 micro g/ml; t(1/2)=9.4 min; 55% aspirin), purified horse serum butyrylcholinesterase (100 micro g/ml; t(1/2)=1.85 min;11% aspirin) and in 10% human plasma solution in the presence of physostigmine (3 micro M). The results indicate that a specific enzyme present in human plasma, probably human butyrylcholinesterase, catalyses aspirin release from isosorbide diaspirinate.

Aspirin↗
PubMed1984

Isosorbide 5-mononitrate and isosorbide 2-mononitrate kinetics after intravenous and oral dosing.

Isosorbide 5-mononitrate (IS-5-MN) and isosorbide 2-mononitrate (IS-2-MN) kinetics were studied in two groups of young healthy subjects after intravenous injection of 5 mg of both and after oral doses of 20 mg of IS-2-MN and 10, 15, and 20 mg of IS-5-MN. Mononitrate plasma levels were measured by GLC with capillary columns. After intravenous injection, IS-5-MN and IS-2-MN plasma levels declined biexponentially and could be described by an open two-compartment body model. Distribution t 1/2 was rapid; 8.6 min for IS-5-MN and 12.5 min for IS-2-MN. Substances were distributed throughout body water; volume of distribution at steady state (Vd ss) was 48 l for IS-5-MN and 55 l for IS-2-MN and elimination t 1/2 was 4.15 hr for IS-5-MN and 1.9 hr for IS-2-MN. Total plasma clearance was 8.5 l/hr for IS-5-MN and 23.2 l/hr for IS-2-MN. After oral doses the mononitrates were rapidly and completely absorbed (absorption t 1/2 ranged from 2.5 to 5 min) from the gastrointestinal tract without first-pass metabolism, i.e., absolute systemic availability was 100%. In the dose range studied, kinetics of the two mononitrates were linear. Compared with isosorbide dinitrate, mononitrate kinetics are different because of greater systemic availability, slower clearance, and smaller Vd ss.

Absorption↗
PubMed1984

Effect of 5-isosorbide mononitrate on isosorbide dinitrate-induced relaxation of rabbit aortic rings.

The ability of isosorbide dinitrate (ISDN) and its two metabolites, 5-isosorbide mononitrate (5-ISMN) and 2-isosorbide mononitrate (2-ISMN), to relax phenylephrine-contracted rabbit aortic rings was compared. The three organic nitrates demonstrated similar efficacy. ISDN was found to be the most potent (median effective dose (ED50); 1.5 X 10(-7) +/- 1.1 X 10(-7) M), followed by 2-ISMN (ED50, 1.8 X 10(-6) +/- 9 X 10(-7) M) and 5-ISMN (ED50, 8.2 X 10(-6) +/- 3.6 X 10(-6) M). The log dose-response curve of ISDN in rabbit aortic rings was constructed in the absence and presence of three fixed concentrations of 5-ISMN (5 X 10(-6), 10(-5), and 3 X 10(-5) M). No shift in the ISDN dose-response curve at high ISDN concentrations was noted in the presence of 5-ISMN. Using the isobolographic method with fixed ISDN/5-ISMN ratio mixtures, no evidence for an antagonistic effect of 5-ISMN on ISDN-induced vasodilation was obtained. Analysis of the fixed ISDN/5-ISMN ratio mixture responses by the median-effect plot showed no antagonistic effect. It is concluded that in rabbit aortic rings 5-ISMN, the major metabolite of ISDN, is not an antagonist of ISDN at a "nitrate receptor," and no support is provided for the hypothesis that the accumulation in plasma of metabolites (e.g., 5-ISMN) with longer half-lives than the parent drug explains tolerance to organic nitrates.

Animals↗
PubMedDate not supplied

Nitrate tolerance: hemodynamic effects of intravenous isosorbide dinitrate after sustained oral isosorbide dinitrate administration.

To determine whether hemodynamic effects of isosorbide dinitrate (ISDN) diminish and disappear during sustained administration, nine patients with recent myocardial infarction received 10 mg of ISDN intravenously before and 1, 4, 12, 24, and 48 weeks after sustained oral administration of 20 mg of the slow-release form of ISDN four times daily. Blood pressure always decreased after intravenous ISDN; the decrease tended to be diminished when preceded by oral ISDN, but no further attenuation in blood pressure was noted. The decrease in blood pressure was associated with consistent and nonsignificant increases in heart rate after intravenous ISDN. Plasma ISDN levels were not affected by prior oral ISDN. Plasma isosorbide 2-mononitrate and isosorbide 5-mononitrate levels were consistently higher when preceded by oral ISDN. The results suggest that the hemodynamic and metabolic properties of ISDN are preserved even after sustained therapy.

Administration, Oral↗
PubMed1993

[Plasma levels of isosorbide dinitrate and its metabolites during intravenous infusion in surgical patients--effect of preoperative administration of isosorbide dinitrate].

Nineteen patients with ischemic heart disease were studied to determine plasma levels of isosorbide dinitrate (ISDN) and its metabolites, isosorbide-2-mononitrate (2-ISMN) and isosorbide-5-mononitrate (5-ISMN) for 6 hrs during intravenous administration of ISDN, using gas chromatography. Differences in plasma levels of these substances were also evaluated in patients with or without preanesthetic medication of ISDN. These patients ranging in ages from 42 to 80 years were administered ISDN intravenously at a rate of 1 micrograms.kg-1 x min-1 during anesthesia and surgery. Preanesthetic administration of ISDN consisted of transdermal application of 40 mg dose. Surgery included gastrectomy, pneumonectomy, extended cholecystectomy, radical mastectomy and so on under either enflurane anesthesia or neuroleptanesthesia. Plasma ISDN levels increased and reached a plateau 3 hrs after the start of intravenous infusion of ISDN in patients of both groups. Plasma 2-ISMN levels increased gradually and reached a plateau 5 hrs after the commencement of intravenous administration of ISDN in patients of both groups. Plasma 5-ISMN levels increased gradually reaching the peak 6 hrs after the start of intravenous infusion of ISDN in both groups. Plasma ISDN, 2-ISMN and 5-ISMN levels were slightly higher in patients who received preanesthetic ISDN than in those who did not receive preanesthetic ISDN. However, there were no statistical differences in plasma ISDN or 2-ISMN levels between the groups except prior to the infusion. On the contrary, plasma 5-ISMN levels were significantly higher in patients who received preanesthetic ISDN than in those who did not receive preanesthetic ISDN for 3 hrs after the start of the infusion.

Adult↗
PubMed1986

Nitro compounds (isosorbide dinitrate, 5-isosorbide mononitrate and glyceryl trinitrate) on the femoral vein and femoral artery.

In organ bath studies, the selectivity of isolated femoral vein and artery of rabbit to isosorbide dinitrate (ISDN), 5-isosorbide mononitrate (ISMN), major metabolite of ISDN, and glyceryl trinitrate (GTN) was compared. The femoral vein and artery contracted by norepinephrine were relaxed by all the nitro compounds dose-dependently. Potency order was GTN greater than ISDN greater than ISMN. The maximum inhibitory responses to the nitrocompounds and their pIC50 values (negative logarithms of doses to induce the 50% response) were greater in the femoral vein than in the femoral artery. For ISMN a 3 times greater sensitivity of femoral vein than of femoral artery was found.

Animals↗
PubMed1987

Effects of nitro compounds, isosorbide dinitrate, 5-isosorbide mononitrate and glyceryl trinitrate on Ca-uptake into Ca-stores and Ca-release from Ca-stores in rabbit isolated femoral veins and femoral arteries.

In organ bath studies, effects of isosorbide dinitrate (ISDN), 5-isosorbide mononitrate (ISMN), a major metabolite of ISDN, and glyceryl trinitrate (GTN) on Ca-uptake into Ca-stores and Ca-release from Ca-stores were tested in the rabbit isolated femoral veins and femoral arteries. ISDN (10(-4) M) and GTN (10(-4) M) inhibited Ca-uptake in the femoral veins but not in the femoral arteries. The selectivity to the femoral veins was not observed in ISMN (10(-3) M) and GTN (3 X 10(-6) M). All the nitro compounds inhibited Ca-release from Ca-stores more effectively in the femoral veins than in the femoral arteries. The present results may explain the selectivity of the nitro compounds to the femoral veins.

Animals↗
PubMed2004

Comparison of the time to onset of action on myocardial ischaemia following intravenous administration of isosorbide dinitrate and 5-isosorbide mononitrate in Chinese patients.

OBJECTIVE: The onset of action of intravenous isosorbide dinitrate (CAS 87-33-2, ISDN) and intravenous 5-isosorbide mononitrate (CAS 16051-77-7, 5-ISMN) were compared by measurement of the indicators of perfusion to ischaemic myocardium. METHODS: Twenty-five patients with coronary heart disease were randomly allocated to receive intravenous ISDN or 5-ISMN. The extent of myocardial ischaemia before infusion and at 3, 15 and 45 min after commencement of infusion was evaluated using 99mTc-MIBI myocardium tomography imaging and electrocardiograms. RESULTS: The perfusion defects were significantly reduced or resolved in 11 patients (84.1%) receiving ISDN and 2 patients (15.38%) receiving 5-ISMN at 3 min. At 15 min the improvement was significantly greater in the ISDN group than in the 5-ISMN group. The improvements of 99mTc-MIBI myocardial uptake ratio and electrocardiograms were statistically significant in the ISDN group at 3 min and 15 min compared to pre-infusion. Although a significant improvement appeared at 15 min in the 5-ISMN group, it was significantly less than that observed in the ISDN group (p < 0.05). After 45 min, there were improvements in ischaemia in both groups with the difference compared to pre-infusion being significant, and there was no statistically significant difference between the ISDN and 5-ISMN group. CONCLUSION: In patients with coronary heart disease with ischaemic episodes the onset of therapeutic activity was more rapid with intravenous ISDN compared to 5-ISMN. ISDN should be the preferred intravenous nitrate for acute ischaemic episodes where a rapid onset of therapeutic action is desired.

Acute Disease↗
PubMed1997

Influence of diet on the single-dose pharmacokinetics of isosorbide 5-mononitrate and sustained-release isosorbide dinitrate.

The influence of diet on the single-dose pharmacokinetics of isosorbide 5-mononitrate (IS-5-MN) and sustained-release isosorbide dinitrate (ISDN) was studied in 8 healthy male volunteers. The subjects received either a low-calorie/low-fat diet (LCFD) or a high-calorie/high-fat diet (HCFD) according to a cross-over schedule and were administered the drug in tablet form after breakfast. The study was conducted first in 8 subjects who received a 20 mg IS-5-MN tablet and then in 6 of these individuals who received a 20 mg sustained-release ISDN tablet. After oral doses of IS-5-MN, the plasma drug levels declined monoexponentially and could be described by a one-compartment open model. There were no significant differences in the pharmacokinetic parameters for IS-5-MN between the LCFD and the HCFD. After administration of sustained-release ISDN, the plasma ISDN levels showed marked variations both between and within individuals. The increase in the mean AUC0-12 values for ISDN with the HCFD was found to exceed 60%, although there was no significant difference between the two diets.

Administration, Oral↗
PubMed1987

Contribution of isosorbide-5-mononitrate, a major metabolite of isosorbide dinitrate (ISDN), to the hemodynamic effect of ISDN administered orally in conscious dogs.

This study was designed to determine the extent, to which isosorbide-5-mononitrate (5-ISMN) contributes to the hemodynamic effect of isosorbide dinitrate (ISDN) in conscious dogs. Test drugs (ISDN or 5-ISMN) were given orally. Either ISDN or 5-ISMN produced a decrease in blood pressure dose-dependently, the decrease in pulse pressure being specific; the pattern of blood pressure change induced by ISDN or 5-ISMN was different from that induced by nifedipine or prazosin. The effect of ISDN (2 mg/kg) was almost equivalent to that of 5-ISMN (4 mg/kg) and the effect of ISDN (4 mg/kg) to that of 5-ISMN (8 mg/kg). After administration of ISDN, both ISDN and 5-ISMN appeared in the plasma, and the effect of ISDN well-correlated with the increase in the plasma concentration of 5-ISMN. Contribution of 5-ISMN to the effect of ISDN was estimated to be about 30% from the value of the plasma concentration of 5-ISMN at 3 to 4 hr after administration, when the maximal response to ISDN occurred. Based on the data of the area under the plasma concentration curve of 5-ISMN (from 0 to 10 hr after administration), the fraction of biotransformation to 5-ISMN from ISDN was calculated to be 73.6 to 76.6% (based on moles). Because the ability of 5-ISMN to decrease pulse pressure was about 1/2 (or 41% based on moles) of that of ISDN, the contribution of 5-ISMN to the effect of ISDN was estimated to be about 30% in total, the value being similar with that estimated at 3 to 4 hr after administration.

Administration, Oral↗