Relationship between pharmacokinetics and pharmacodynamics of molsidomine and its metabolites in humans

doi:10.1016/0002-8703(85)90671-4

American Heart Journal

Volume 109, Issue 3, Part 2, March 1985, Pages 644-648

https://doi.org/10.1016/0002-8703(85)90671-4 Get rights and content

Abstract

The pharmacokinetic properties and hemodynamic effect of molsidomine and its pharmacologically active metabolite SIN-1 were investigated in 13 healthy volunteers following single oral doses. Hemodynamic changes were measured by finger plethysmography (peripheral arterial resistance), impedance plethysmography (venous distensibility), heart rate, and blood pressure. Plasma concentrations of molsidomine, SIN-1, and SIN-1C were measured by means of high-pressure liquid chromatography. Oral administration of rapidly dissolving tablets of molsidomine (2 tablets of 4 mg), a sustained-release form of molsidomine (8 mg), and SIN-1 (4 mg) caused an increase of the $a b$ ratio of the finger plethysmogram and an increase of the venous distensibility. Heart rate and blood pressure remained unaffected. The time course of the peripheral arterial effect mimicked the time course of plasma concentrations of molsidomine and SIN-1. Similar to the results in animals, molsidomine was metabolized in humans to SIN-1 and subsequently degraded to the inactive metabolite SIN-1C. The kinetic profile of both metabolites could be followed in the plasma. The rate-limiting step in the metabolic sequence of molsidomine was found to be enzymatic hydrolysis and decarboxylation of molsidomine to SIN-1. Concentration-response curves of the $a b$ ratio of the finger plethysmogram showed that the plasma concentrations required to produce a definite effect are much higher for molsidomine than for SIN-1. This shows that the pharmacodynamically active form of molsidomine in humans is the metabolite SIN-1. The changes in the finger plethysmogram produced by SIN-1 suggest that in addition to the effect on the venous site, SIN-1 also dilates the peripheral arterial site.

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Cited by (24)

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2022, Comprehensive Pharmacology
Cardiovascular diseases are among the leading causes of death in industrialized countries. Although our understanding of the development of atherosclerosis has grown in recent decades, the treatment of coronary heart disease, myocardial infarction and associated left heart failure, still remains a medical challenge.
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This article focuses on standard and new experimental treatments of coronary artery disease. Special attention was payed to organic nitrates and other nitric oxide donors. We include aspects concerning the mechanisms of action, bioactivation, tachyphylaxis (tolerance development) and pharmacokinetic data of the different drugs.
Moreover, new experimental approaches are mentioned, some of which are promising and may find their way into the clinic.
Pharmacokinetics and pharmacodynamics of nitric oxide mimetic agents
2019, Nitric Oxide - Biology and Chemistry
Citation Excerpt :
Although release of NO from molsidomine requires enzymatic bioactivation, the development of tolerance is not a clinically relevant problem because tolerance is much less pronounced than observed for nitrates [50,51]. Oral administration of molsidomine (2 or 4 mg) to healthy volunteers studied the relationship between plasma concentrations of molsidomine and SIN 1 with peripheral arterial resistance (i.e., in the form of finger plethysmography), venous distensibility (i.e., impedance plethysmography), heart rate, and blood pressure [52]. SIN 1 was confirmed to be the pharmacodynamically active form of molsidomine and the rate limiting step for prodrug breakdown was enzymatic hydrolysis and decarboxylation (i.e., conversion of molsidomine to SIN 1).
Drug discovery focusing on NO mimetics has been hamstrung due to its unconventional nature. Central to these challenges is the fact that direct measurement of molecular NO in biological systems is exceedingly difficulty. Hence, drug development of NO mimetics must rely upon measurement of the NO donating specie (i.e., a prodrug) and a downstream marker of efficacy without directly measuring the molecule, NO, that is responsible for biological effect. The focus of this review is to catalog in vivo attempts to monitor the pharmacokinetics (PK) of the NO donating specie and the pharmacodynamic (PD) readout of NO bioactivity.
The ESPRIM trial: short-term treatment of acute myocardial infarction with molsidomine
1994, The Lancet
Summary
Previous small clinical trials have suggested that treatment with nitric oxide donors in suspected myocardial infarction can reduce mortality by 30-35%. To confirm this finding in a large-scale trial, we compared molsidomine and its active metabolite linsidomine (a nitric oxide donor) with placebo in 4017 patients with acute myocardial infarction.
In our trial, patients without signs of overt heart failure (Killip III/IV) were randomly assigned in a double-blind design within 24 h of symptom onset to receive linsidomine 1 mg/h intravenously for 48 h, followed by 16 mg molsidomine by mouth daily for 12 days (n=2007), or an identical placebo (n=2010). All other treatments could be used at the responsible physician's discretion with the exception of systematic vasodilator treatment. The molsidomine and placebo groups showed similar all-cause 35-day mortality (168 [8·4%] vs 176 [8·8%] deaths, p=0·66), and adjustment for baseline variables in a Cox model had no effect. Similarly, we found no difference for long-term mortality (mean follow-up 13 months; 294 [14·7%] vs 285 [14·2%] deaths, p=0·67). The two groups showed similar frequencies of major and minor adverse events; only headache was significantly more common in the molsidomine group.
Changes in treatment practices and the lower risk profile of our study subjects than of participants in previous trials may explain the results. It is still not clear whether nitric oxide donors can improve survival in higher-risk myocardial infarction patients.
Molsidomine in the treatment of coronary disease
1987, La Revue de medecine interne
La molsidomine, vasodilatateur à prédominance d'action veineuse, a été largement utilisée depuis plus de 5 ans dans le traitement des diverses formes cliniques de la maladie coronaire. Le mécanisme fondamental de son effet antiangineux est une diminution de la consommation en oxygène du myocarde liée à un abaissement de la pression télédiastolique du ventricule gauche conséquence directe de son effet vasodilatateur. Il s'y surajoute une dilatation directe des gros troncs coronaires épicardiques pouvant rendre compte d'une partie de ses effets thérapeutiques dans l'angor instable et dans l'angor vasospastique. L'efficacité de la molsidomine a été évaluée, lors d'études contrôlées, contre placebo ou comparativement à un antiangineux de référence, dans l'angor d'effort, dans l'angor instable et dans l'angor vasospastique. L'efficacité de la molsidomine a également été établie dans les formes aiguës et chroniques d'insuffisance ventriculaire gauche d'origine ischémique. La pharmacocinétique de la molsidomine caractérisée par une forte biodisponibilité orale rend compte d'une faible variabilité interindividuelle des effets pharmacodynamiques. Contrairement à celle des dérivés nitrés, l'administration au long cours de la molsidomine ne semble pas provoquer d'épuisement progressif de l'effet antiangineux du fait du développement d'une tolérance pharmacologique. Enfin, la molsidomine exerce sur plusieurs modèles expérimentaux un net effet antiagrégant plaquettaire. Les implications thérapeutiques de cette particularité pharmacodynamique restent à évaluer par des études cliniques contrôlées.
Molsidomine, a predominantly venous vasodilator, has been widely used for more than 5 years to treat various types of coronary disease. The basic mechanism of its anti-anginal effect is a reduction in myocardial oxygen consumption due to a fall in left ventricular end-diastolic pressure resulting from the vasodilator action of the drug. To this may be added direct dilatation of the main coronary vessels on the surface of the heart, which may account for part of its therapeutic effects in unstable and vasospastic angina. The effectiveness of molsidomine has been evaluated by controlled drug versus placebo or drug versus reference anti-anginal drug studies in 3 types of angina pectoris: exertion, unstable and vasospastic. The usefulness of the drug has also been established in acute and chronic left ventricular failure of ischaemic origin. Because of its high bioavailability when administered orally, molsidomine shows little inter-individual variations in its pharmacodynamic effects. Unlike nitrates, it can be administered for long period without gradual loss of activity with time. Finally, on several experimental models molsidomine has been shown to exert an antiplatelet effect, but the therapeutic implications of this finding have yet to be evaluated.
Summary and comments: Sessions I and II
1985, American Heart Journal
Exercise tolerance in coronary patients: Randomized trial of two-week treatment with molsidomine versus placebo
1985, American Heart Journal
Using a randomized, double-blind, crossover protocol, we compared the effects of oral molsidomine (Corvaton, 6 mg/day) and placebo, administered alternately for two 14-day periods, on the exercise tolerance of 25 outpatients with coronary heart disease. Resting heart rate and oxygen consumption increased by 6.8% (p < 0.005) and 12.6% (p < 0.01), while peripheral systolic blood pressure was reduced by 5.1% (p < 0.05). At submaximal workloads, systolic and diastolic blood pressures were reduced by 5.6% (p < 0.001) and 6.1% (p < 0.001), the pressure-rate product was reduced by 8.5% (p < 0.05), and ST segment depression was reduced by 40.0% (p < 0.005). At maximal exercise level, mechanical power increased by 32.4% (p < 0.001) and oxygen consumption by 15.5% (p < 0.005), while ST segment depression was reduced by 30.6% (p < 0.001). No alteration was found in postexercise lung function tests. It is concluded that molsidomine reduces myocardial ischemia at both submaximal and maximal work levels and increases exercise tolerance significantly. These effects could be related to reduced myocardial oxygen requirements, reflected in a lower pressure-rate product at submaximal exercise and perhaps enhanced by a lower preload, which, moreover, would favor coronary flow in subendocardial layers. The drug has no adverse bronchopulmonary effects.

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Relationship between pharmacokinetics and pharmacodynamics of molsidomine and its metabolites in humans

Abstract

J Chromatogr

Kinetics of pharmacologic response

Pharmacol Ther

A quantitative determination method of molsidomine and its metabolite in plasma by high performance liquid chromatography

J Takeda Res Lab