Metabolism of OR-1896, a metabolite of levosimendan, in rats and humans.
OR-1896 is a pharmacologically active, long-lived metabolite of levosimendan. In the current study, the metabolism of (14)C-labelled OR-1896 was investigated in six healthy men after intravenous infusion over 10 min and in male rats after an intravenous bolus dose. In human plasma, the only (14)C-compounds detected were (14)C-OR-1896 and its deacetylated form, (14)C-OR-1855, in varying proportions in different subjects. In rat plasma >93% of radioactivity was associated with OR-1896. Radioactivity was mainly excreted to urine in both rats (about 69% of the dose) and humans (about 87% of the dose). OR-1896 was a major urinary compound in both humans and rats. Another major human metabolite was hypothesized as N-conjugated OR-1855. Other human and rat urinary biotransformation products were characterized as N-hydroxylated OR-1896 and N-hydroxylated OR-1855, as well as glucuronide or sulphate conjugates of N-hydroxyl OR-1896. The main difference between rat and human metabolism was a lower amount of OR-1855-related metabolites in the rats. In human faecal homogenates, only OR-1896 and OR-1855 were detected, whereas rat faecal metabolite profile was similar to that in urine.
Koskinen
M
M
Orion Corporation Orion Pharma, R&D, Department of Pharmacokinetics and Bioanalytics, Espoo, Finland. mikko.koskinen@orionpharma.com
Puttonen
J
J
Pykäläinen
M
M
Vuorela
A
A
Lotta
T
T
D000081:Acetamides / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D000328:Adult; D000818:Animals; D002316:Cardiotonic Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D006835:Hydrazones / Q000493:pharmacokinetics / Q000652:urine; D008297:Male; D008875:Middle Aged; D011724:Pyridazines / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077464:Simendan
D000081:Acetamides; 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