Pharmacokinetics of levosimendan
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1
Aristotle University of Thessaloniki, Second Cardiology Department, Greece
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2
Aristotle University of Thessaloniki, Department of Pharmacology, Greece
Introduction. Levosimendan is a calcium sensitizer with inotropic and vasodilatory actions mediated by the sensitization of calcium dependent contractile proteins, opening of potassium channels and inhibition of phosphodiesterase-3. Ιt is indicated in patients with symptomatic low cardiac output, heart failure (HF) secondary to cardiac systolic dysfunction without severe hypotension. Levosimendan does not increase myocardial oxygen demand and has anti-inflammatory and antiapoptotic functions.
Pharmacokinetics. Oral levosimendan has high bioavailability (approximately equal to 85%), and transdermal administration can be significantly increased by formulation modification. In clinical practice it is administered intravenously (12-24 μg/kg loading dose followed by 0.05-0.2 μg/kg/min for 24 hours, adjusted for response and tolerability). Levosimendan pharmacokinetics is linear at the therapeutic dose range. The drug has total clearance 175-250 mL/h/kg, half-life about 1.5 hours and peak concentrations are achieved within 4 h. Its prolonged action (up to 7-9 days) is not due to the drug itself but mainly due to its active metabolite OR-1896 (approximately 80 hours half life). Other metabolites with possible pharmacologic effects are N-conjugated OR-1855, N-hydroxylated OR-1855, N-hydroxylated OR-1896, O-glucuronide OR-1896 and O-sulfate of N-hydroxylated OR-1896. It is excreted into the small intestine and metabolized by intestinal bacteria to OR-1855. This metabolite is further metabolised by acetylation to OR-1896. The circulating metabolites OR-1855 and OR-1896 are formed slowly, and their maximum concentrations are seen on average 2 days after stopping a 24-hour infusion. The haemodynamic effects after levosimendan administration are similar between fast and slow acetylators despite the fact that the enzyme N-acetyltransferase-2, which is responsible for the metabolism of OR-1855 to OR-1896, is polymorphically distributed in the population.
Levosimendan pharmacokinetics is also similar in healthy people and patients with HF and remain relatively unaltered by age, sex, moderate hepatic impairment and other organ dysfunction. After a continuous infusion for 7 days, they were found to be similar to those observed previously in single dose studies. Bodyweight influenced the clearance and the central volume of distribution, which in practice is accounted by weight adjusting doses. None of the other covariates, including digoxin and beta-blocking agents, influenced the pharmacokinetics of levosimendan significantly.
Conclusion. Levosimendan has a special pharmacokinetic interest, because it is one of the few drugs used in cardiovascular therapeutics, with prolonged action due to its metabolites only and not to the drug itself.
Keywords:
levosimendan,
pharmacokinetics,
Heart Failure
Conference:
8th Southeast European Congress on Xenobiotic Metabolism and Toxicity - XEMET 2010, Thessaloniki, Greece, 1 Oct - 5 Oct, 2010.
Presentation Type:
Poster
Topic:
Food, drugs and environmental xenobiotics
Citation:
Bostanitis
I,
Tsalidou
M,
Boudonas
G and
Sakadamis
G
(2010). Pharmacokinetics of levosimendan.
Front. Pharmacol.
Conference Abstract:
8th Southeast European Congress on Xenobiotic Metabolism and Toxicity - XEMET 2010.
doi: 10.3389/conf.fphar.2010.60.00109
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Received:
28 Oct 2010;
Published Online:
04 Nov 2010.
*
Correspondence:
Dr. Ioannis Bostanitis, Aristotle University of Thessaloniki, Second Cardiology Department, Thessaloniki, Greece, bostangiannis@yahoo.gr