Pharmacokinetics and excretion balance of OR-1896, a pharmacologically active metabolite of levosimendan, in healthy men.
OBJECTIVE
To investigate the pharmacokinetics and excretion balance of [(14)C]-OR-1896, a pharmacologically active metabolite of levosimendan, in six healthy male subjects. In addition, pharmacokinetic parameters of total radiocarbon and the deacetylated congener, OR-1855, were determined.


METHODS
OR-1896 was administered as a single intravenous infusion of 200 microg of [(14)C]-OR-1896 (specific activity 8.6 MBq/mg) over 10 min. The pharmacokinetic parameters were calculated by three-compartmental methods.


RESULTS
During the 14-day collection of urine and faeces, excretion (+/-S.D.) averaged 94.2+/-1.4% of the [(14)C]-OR-1896 dose. Mean recovery of radiocarbon in urine was 86.8+/-1.9% and in faeces 7.4+/-1.5%. Mean terminal elimination half-life of OR-1896 (t(1/2)) was 70.0+/-44.9 h. Maximum concentrations of OR-1855 were approximately 30% to that of OR-1896. Total clearance and the volume of distribution of OR-1896 were 2.0+/-0.4 l/h and 175.6+/-74.5l, respectively. Renal clearances of OR-1896 and OR-1855 were 0.9+/-0.4 l/h and (5.4+/-2.3)x10(-4) l/h, respectively.


CONCLUSIONS
This study provides data to demonstrate that nearly one half of OR-1896 is eliminated unchanged into urine and that the active metabolites metabolite of levosimendan remain in the body longer than levosimendan. The remaining half of OR-1896 dose is eliminated through other metabolic routes, partially through interconversion back to OR-1855 with further metabolism of OR-1855. Given the fact that the pharmacological activity and potency of OR-1896 is similar to levosimendan, these results emphasize the clinical significance of OR-1896 and its contribution to the long-lasting effects of levosimendan.
Puttonen
Jaakko
J
Research and Development, Orion Pharma, P.O. Box 1780, FIN-70701 Kuopio, Finland. jaakko.puttonen@quintiles.com
Laine
Tarmo
T
Ramela
Meri
M
Häkkinen
Sari
S
Zhang
Wenhui
W
Pradhan
Rajendra
R
Pentikäinen
Pertti
P
Koskinen
Mikko
M
D000081:Acetamides / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D000328:Adult; D001944:Breath Tests; D002250:Carbon Radioisotopes; D005243:Feces / Q000737:chemistry; D006801:Humans; D006835:Hydrazones / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008968:Molecular Conformation; D011724:Pyridazines / Q000378:metabolism* / Q000493:pharmacokinetics* / Q000652:urine; D012016:Reference Values; D000077464:Simendan; D013997:Time Factors
D000081:Acetamides; D002250:Carbon Radioisotopes; D006835:Hydrazones; C414222:N-(4-(4-methyl-6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenyl)acetamide; D011724:Pyridazines; D000077464:Simendan