European Journal of Pharmaceutical Sciences 23 (2004) 213–222 Pharmacokinetics of levosimendan and its active metabolite OR-1896 in rapid and slow acetylators Saila Antila a , Ullamari Pesonen b , Lasse Lehtonen a,∗ , Pasi Tapanainen c , Hanna Nikkanen a , Katja Vaahtera c , Harry Scheinin d a Orion Pharma, Research Center, Espoo, Finland b Department of Pharmacology and Clinical Pharmacology, University of Turku, Turku, Finland c Clinical Research Services Turku (CRST), University of Turku, Turku, Finland d Department of Anesthesiology, Turku PET Centre, Turku University Hospital, Turku, Finland Received 13 January 2004; received in revised form 8 June 2004; accepted 5 July 2004 Available online 11 September 2004 Abstract 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 g/(kg min)) i.v. infusion for 24 h in six rapid and six slow acetylators based on N-acetyltransferase 2 genotyping. At the end of the infusion, a small amount (2.5 g/kg) of 13 C-labeled OR-1896 was administered by i.v. infusion for 10min. 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 4–8 h 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 24 h 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. © 2004 Elsevier B.V. All rights reserved. Keywords: Levosimendan; Pharmacokinetics; Metabolism; Acetylation; Genotyping ∗ Corresponding author. Present address: Department of Clinical Phar- macology, University of Helsinki, Helsinki University Central Hospital, P.O. Box 281, HUS 00029 Helsinki, Finland. Tel.: +358 9 471 72773; fax: +358 9 471 72748. E-mail address: lasse.lehtonen@hus.fi (L. Lehtonen). 1. Introduction Levosimendan is developed for the treatment of conges- tive heart failure. It is a novel calcium sensitizer, which exerts positive dose- and time-dependent inotropic effects in the my- ocardium and induces coronary vasodilatation (Hasenfuss et al., 1998). These effects are related to several distinct pharma- cological properties. Levosimendan enhances the sensitivity of the cardiac myofilaments to calcium by binding to troponin 0928-0987/$ – see front matter © 2004 Elsevier B.V. All rights reserved. doi:10.1016/j.ejps.2004.07.005