Pharmacokinetics of levosimendan and its active metabolite OR-1896 in rapid and slow acetylators.
OBJECTIVE
The purpose of this study was to investigate the pharmacokinetics of levosimendan and to determine the primary pharmacokinetic parameters of the pharmacologically active metabolite OR-1896 in rapid and slow acetylators.


METHODS
Levosimendan was administered as a constant rate (0.1 microg/(kg min)) i.v. infusion for 24h in six rapid and six slow acetylators based on N-acetyltransferase 2 genotyping. At the end of the infusion, a small amount (2.5 microg/kg) of (13)C-labeled OR-1896 was administered by i.v. infusion for 10 min. Blood samples were taken at predefined sampling points 14 days post-infusion and levosimendan and its metabolite concentrations were determined by LC-MS/MS.


RESULTS
Steady-state concentrations of levosimendan were achieved within 4-8h and no differences were found in the pharmacokinetics of the parent compound between the rapid and slow acetylators. The maximum concentrations of amino phenylpyridazinone metabolite OR-1855 and N-acetylated conjugate OR-1896 were observed approximately 24h after terminating the infusion. AUC of OR-1896 was approximately 3.5 times higher in the rapid acetylators compared to the slow acetylators (P = 0.002, 95% confidence interval for group ratio from 2.0 to 8.2). The mean +/- S.D. fraction of levosimendan metabolized to OR-1896 was 6.8 +/- 2.8% in the rapid and 4.3 +/- 2.4% in the slow acetylators (P = 0.12). (13)C-OR-1855 concentrations were detected in plasma after administration of (13)C-OR-1896 indicating deacetylation from OR-1896 to OR-1855.


CONCLUSIONS
Plasma OR-1896 levels during and after levosimendan treatment are dependent on the acetylation status of the subject-rapid acetylators having 3.5 times higher concentrations than slow acetylators.
Antila
Saila
S
Orion Pharma, Research Center, Espoo, Finland.
Pesonen
Ullamari
U
Lehtonen
Lasse
L
Tapanainen
Pasi
P
Nikkanen
Hanna
H
Vaahtera
Katja
K
Scheinin
Harry
H
D000081:Acetamides / Q000378:metabolism*; D000107:Acetylation; D000328:Adult; D019540:Area Under Curve; D001191:Arylamine N-Acetyltransferase / Q000235:genetics / Q000378:metabolism*; D001798:Blood Proteins / Q000378:metabolism; D002250:Carbon Radioisotopes; D002316:Cardiotonic Agents / Q000493:pharmacokinetics*; D005838:Genotype; D006207:Half-Life; D006801:Humans; D006835:Hydrazones / Q000378:metabolism / Q000493:pharmacokinetics*; D007262:Infusions, Intravenous; D008297:Male; D011485:Protein Binding; D011724:Pyridazines / Q000378:metabolism* / Q000493:pharmacokinetics*; D000077464:Simendan; D013997:Time Factors
D000081:Acetamides; D001798:Blood Proteins; D002250:Carbon Radioisotopes; D002316:Cardiotonic Agents; D006835:Hydrazones; C414222:N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide; D011724:Pyridazines; D000077464:Simendan; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human