Site dependent bioavailability and metabolism of levosimendan in dogs

Antila, Saila; Huuskonen, Hannele; Nevalainen, Timo; Kanerva, Harri; Vanninen, Paula; Lehtonen, Lasse

doi:10.1016/s0928-0987(99)00048-2

Cited by 48 publications

(24 citation statements)

References 6 publications

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“…About 5% of the drug is metabolized in the intestine into OR-1855 and subsequently acetylated in the liver to form OR-1896. 16 This second metabolite has a half-life of approximately 80 hours and shares most of levosimendan's hemodynamic actions, 17 allowing for long-lasting effects after a 24-hour infusion. Acetylation of OR-1855 into OR-1896 shows individual variation; while most Caucasians are slow acetylators, Asians are typically fast acetylators.…”

Section: Mechanism Of Action and Pharmacokineticsmentioning

confidence: 99%

Levosimendan: The current situation and new prospects

Moreno

Tavares-Silva

Lourenço

et al. 2014

Revista Portuguesa de Cardiologia

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Levosimendan is a pyridazinone-dinitrile derivative with positive inotropic and vasodilatory effects that has beneficial effects on myocardial performance. In previous randomized studies levosimendan improved hemodynamics and clinical course, but its effect on prognosis is still unclear. This important issue has limited its use. Although primarily used in the management of acute heart failure syndromes, this new inotropic agent may play a role in other clinical conditions. This review aims to summarize current knowledge on levosimendan and to present future prospects for the use of this drug.

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Section: Mechanism Of Action and Pharmacokineticsmentioning

confidence: 99%

Levosimendan: The current situation and new prospects

Moreno

Tavares-Silva

Lourenço

et al. 2014

Revista Portuguesa de Cardiologia

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“…Gut microbial cleavage of a hydrazine/hydrazone has been rare, however. Antila et al (1999) suggested that the hydrazone linkage of levosimendan was reductively cleaved by microbes in the lower gastrointestinal tract in dogs, A cleavage product of levosimendan [(R)-6-(4-aminophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one (OR-1855)] was then absorbed and further metabolized to a pharmacologically active component in humans (Antila et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Investigations of Hydrazine Cleavage of Eltrombopag in Humans

Deng¹,

Rogers²,

Sychterz³

et al. 2011

Drug Metab Dispos

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ABSTRACT:After oral administration to humans, eltrombopag undergoes extensive cleavage of its hydrazine linkage to metabolites, which are exclusively eliminated in urine. In vitro, the cleavage pathway was not detected in systems using cytochrome P450 enzymes, renal or hepatic microsomes, or hepatocytes but was readily evident after anaerobic incubation with rodent cecal contents or human fecal homogenate. Antibiotic treatment in vitro and in vivo inhibited eltrombopag cleavage, further indicating that cleavage is via gut microbes. Antibiotic treatment did not alter the systemic exposure of eltrombopag in mice. Oral and intravenous pharmacokinetic characterization in the mice with one of the cleavage products indicated that it was readily absorbed, conjugated, and eliminated in urine, consistent with its fate after oral administration of eltrombopag. Variation in this microbial pathway, for example by antibiotic cotherapy, is unlikely to be clinically significant.

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“…The metabolites considerably prolong the hemodynamic effects of levosimendan because the half-life of OR-1896 is 77 to 81 hours [29•,30]. The presence of the active metabolites even after intravenous dosing indicates enterohepatic circulation of the drug or its conjugates [31].…”

Section: Mci-154mentioning

confidence: 99%

Levosimendan: A calcium-sensitizing agent for the treatment of patients with decompensated heart failure

Lehtonen

2004

Curr Heart Fail Rep

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Levosimendan is a new inodilator. Its mechanism of action includes calcium sensitization of contractile proteins and the opening of adenosine triphosphate-dependent K channels. The combination of positive inotropy with anti-ischemic effects of K-channel opening offers potential benefits in comparison with currently available intravenous inotropes, which are contraindicated in patients with ongoing myocardial ischemia. Levosimendan has been extensively studied in various animal models of heart failure, in which the drug has increased contractility without adverse effects on diastolic function. These results have been repeated in patients with heart failure, in whom levosimendan dose-dependently increases cardiac output and reduces pulmonary capillary wedge pressure. The active metabolite of levosimendan (OR-1896) significantly prolongs the duration of the hemodynamic effects of the therapeutic 24-hour levosimendan infusion. Levosimendan has been studied in two major trials with decompensated patients (LIDO and RUSSLAN), in which it showed outcome benefits in comparison with dobutamine and placebo, respectively. A third comparative study (CASINO) recently suggested mortality benefits with levosimendan over placebo and dobutamine. Currently, two large prospective trials (SURVIVE and REVIVE) in patients who are hospitalized because of worsening heart failure are underway. These trials will conclusively prove whether levosimendan should be added to the standard treatment in patients who are hospitalized because of cardiac decompensation.

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Site dependent bioavailability and metabolism of levosimendan in dogs

Cited by 48 publications

References 6 publications

Levosimendan: The current situation and new prospects

Levosimendan: The current situation and new prospects

Investigations of Hydrazine Cleavage of Eltrombopag in Humans

Levosimendan: A calcium-sensitizing agent for the treatment of patients with decompensated heart failure

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