Site dependent bioavailability and metabolism of levosimendan in dogs
Introduction
Several physiological, biochemical and physicochemical factors may affect bioavailability of the drug. Bioavailability may be reduced for instance by presystemic first pass metabolism in the gastrointestinal tract. In recent decades many different in vitro, in situ and in vivo methods have been developed to study the extent of the drug entering the systemic circulation. One of these in vivo methods is a cannulated dog model. Cannulas are situated in different parts of the gastrointestinal tract. Solid drugs are administered directly through these cannulas to the intestine which allows site specific bioavailability to be evaluated (Rubinstein et al., 1988; Lemaire et al., 1991). Direct administration to the gastrointestinal tract is also useful for studying presystemic metabolism.
Levosimendan is a molecule developed for the treatment of congestive heart failure. The drug exerts positive inotropic and peripheral vasodilatory effects that are related to several distinct pharmacological properties. Levosimendan enhances the sensitivity of the myofilaments to calcium by binding to troponin C (Pollesello et al., 1994). It acts also as an agonist of APT-dependent potassium channels in myocytes of the blood vessels thus inducing vasodilation (Yokoshiki et al., 1997).
Bioavailability of levosimendan is high. About 85% of levosimendan was absorbed in humans after an oral solution, conventional tablets and capsule formulations (Sandell et al., 1995, Sundberg et al., 1998). However, after a slow release tablet, levosimendan’s bioavailability was reduced to 31%. Also, formation of a plasma metabolite OR-1855 was ten times higher after the slow release formulation compared to the other orally administered formulations (Sundberg et al., 1998). This metabolite OR-1855 is formed from levosimendan most probably in the intestine by a reduction reaction. In humans the metabolite OR-1855 is further acetylated to OR-1896 and this latter metabolite has shown to have similar pharmacological properties as levosimendan (unpublished data).
The purpose of this study was to investigate how the administration of levosimendan to different parts of the gastrointestinal tract affects the bioavailability of levosimendan in dogs and to evaluate the formation of metabolite OR-1855 after these different administration routes. Furthermore, the pharmacokinetic parameters for levosimendan after intravenous dosing in dogs were characterised and the tissue distribution was studied.
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Preparation of animals
The study was conducted at the National Laboratory Animal Center, University of Kuopio, Finland. Five female and five male beagle dogs were used in the study. At the onset of the study the dogs were 14 months of age and the mean body weight (±SD) of the females was 9.6±1.2 kg and of the males was 11.7±1.7 kg.
Intestinal access port catheters (IAP) that were modified silastic vascular-access port (VAP) catheters, had been surgically placed in the duodenum, jejunum and ileum in all the dogs about
Levosimendan
Levosimendan was eliminated rapidly after intravenous dose and after administration to the gastrointestinal tract (Fig. 1). Mean±SD terminal elimination half-life was 0.89±0.30 h and total clearance was 3.37±0.67 ml/min/kg after intravenous infusion (Table 1). The bioavailability of levosimendan was high ranging from 71 to 86% after different administration routes (Table 2).
A statistically significant difference in AUC was seen between dosing by the gastric tube and duodenal administration (P
Discussion
Two circulating metabolites of levosimendan have been identified from human plasma. Levosimendan is first reduced to an amine metabolite OR-1855 and this metabolite is further acetylated to a metabolite called OR-1896. This latter metabolite has shown to have similar pharmadynamic properties as the parent drug and, therefore, it has been essential to study the mechanism and factors which might contribute to the formation of these metabolites.
N-acetyltransferase is most probably involved in the
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2009, Annals of Thoracic SurgeryCitation Excerpt :The plasma levels of the active levosimendan metabolites peaked at 6 days instead of the previously observed 2 to 4 days in the heart failure population [29]. The reason for this altered formation of the metabolites may be related to the use of prophylactic broad-spectrum antibiotics and a consequently diminished amount of intestinal bacteria, which are known to be essential for the formation of the metabolites [31]. Considering the potential clinical effect of our study, the main limitation is that it did not have an active control.
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present address: Verifin, University of Helsinki, Helsinki, Finland