Pharmacokinetics and excretion balance of OR-1896, a pharmacologically active metabolite of levosimendan, in healthy men.

Abstract 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 μg 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 ± 74.5 l, respectively. Renal clearances of OR-1896 and OR-1855 were 0.9 ± 0.4 l/h and (5.4 ± 2.3) × 10 −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.