Pharmacokinetics of levosimendan and its active metabolite OR-1896 in rapid and slow acetylators

Pharmacologically Active Drug Metabolites: Impact on Drug Discovery and Pharmacotherapy

“…While the half-life of levosimendan is short (;1 hour), the active metabolite has a half-life of a few days, and the beneficial effect is observed for considerably longer than what the parent half-life would indicate, suggesting an important role for OR-1896 in the extended duration of activity (Antoniades et al, 2007). In contrast to this, no apparent difference in efficacy has been observed between poor and extensive acetylators despite a difference in exposure to OR-1986 between the two groups (Antila et al, 2004;Kivikko et al, 2011). Delineating the relative contributions of OR-1896 to levosimendan is not straightforward; the pharmacokinetics are such that during the intravenous infusion, the parent drug concentrations are far greater than the …”

Assessment of sustained effects of levosimendan and dobutamine on left ventricular systolic functions by using novel tissue Doppler derived indices in patients with advanced heart failure

“…Levosimendan has a half-life of approximately 1 h [11], but levosimendan's active metabolites are expected to sustain its effects up to 2 weeks [3]. Dobutamine has a short half-life and has no known active metabolite [4], but it has been suggested that after short-term infusion, the benefit can last for 30 days or more; this phenomenon is called the "dobutamine holiday" [12].…”

“…It exerts positive inotropic effects by binding cardiac troponin C and sensitizing cardiac myofilaments to calcium without increasing intracellular calcium concentrations [2]. The active metabolite of levosimendan peaks approximately 3 days after the start of drug infusion and has a halflife of approximately 80 h; thus the drug's action is expected to last for 2 weeks [3]. Dobutamine has a serum half-life of 2 min and has no known active metabolite [4].…”

Investigations of Hydrazine Cleavage of Eltrombopag in Humans

“…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).…”