Pharmacokinetics of Pimobendan and Its Metabolite O-Desmethyl-Pimobendan Following Rectal Administration to Healthy Dogs

Her, Jiwoong; Kuo, Kendon; Winter, Randolph L.; Cruz‐Espindola, Crisanta; Bacek, Lenore M.; Boothe, Dawn M.

doi:10.3389/fvets.2020.00423

Cited by 8 publications

(13 citation statements)

References 26 publications

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“…In the current study, pimobendan was given by injection; therefore, the C max of ODMP is 3.4 times higher while the T max is 5.6 times faster than those of the previous study. In addition, the half-life of pimobendan and ODMP in this study was shorter while the AUC was presumably the same level based on data provided in the previous study ( 37 ).…”

Section: Discussionsupporting

confidence: 76%

“…In this study, the injectable pimobendan provides immediately positive inotropic effect which is suitable for dogs presenting with acute CHF. Previous study in healthy dogs demonstrated that the rectal administration of pimobendan at a dose of 0.5 mg/kg provides rapid absorption and achieves therapeutic plasma concentration which may be suitable for dog with CHF ( 37 ). In that study, the T max and C max of ODMP were 1.7 ± 1.1 h and 8.8 ± 4.8 ng/mL, respectively.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacodynamics and Pharmacokinetics of Injectable Pimobendan and Its Metabolite, O-Desmethyl-Pimobendan, in Healthy Dogs

et al. 2021

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Objectives: This study was designed to thoroughly evaluate the effects of bolus pimobendan at a dose of 0.15 mg/kg on cardiac functions, hemodynamics, and electrocardiographic parameters together with the pharmacokinetic profile of pimobendan and its active metabolite, o-desmethyl-pimobendan (ODMP), in anesthetized dogs.Methods: Nine beagle dogs were anesthetized and instrumented to obtain left ventricular pressures, aortic pressures, cardiac outputs, right atrial pressures, pulmonary arterial pressures, pulmonary capillary wedge pressures, electrocardiograms. After baseline data were collected, dogs were given a single bolus of pimobendan, and the pharmacodynamic parameters were obtained at 10, 20, 30, 60, and 120 min. Meanwhile, the venous blood was collected at baseline and 2, 5, 10, 20, 30, 60, 120, 180, 360, and 1,440 min after administration for the determination of pharmacokinetic parameters.Results: Compared with baseline measurements, the left ventricular inotropic indices significantly increased in response to intravenous pimobendan, as inferred from the maximum rate of rise in the left ventricular pressure and the contractility index. Conversely, the left ventricular lusitropic parameters significantly decreased, as inferred from the maximum rate of fall in the left ventricular pressure and the left ventricular relaxation time constant. Significant increases were also noted in cardiac output and systolic blood pressure. Decreases were observed in the systemic vascular resistance, pulmonary vascular resistance, left ventricular end-diastolic pressure, pulmonary capillary wedge pressure, right atrial pressure, and pulmonary arterial pressure. The heart rate increased, but the PQ interval decreased. There was no arrhythmia during the observed period (2 h). The mean maximum plasma concentration (in μg/L) for ODMP was 30.0 ± 8.8. Pimobendan exerted large volume of distribution ~9 L/kg.Conclusions: Intravenous pimobendan at the recommended dose for dogs increased cardiac contraction and cardiac output, accelerated cardiac relaxation but decreased both vascular resistances. These mechanisms support the use of injectable pimobendan in acute heart failure.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Pharmacodynamics and Pharmacokinetics of Injectable Pimobendan and Its Metabolite, O-Desmethyl-Pimobendan, in Healthy Dogs

et al. 2021

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“…This may be due mainly to the differences in the dosages given to the dogs. It is also known that differences in the design of experiments (e.g., analytical method, dosage, and age of subjects) or the effects of different formulations may lead to such discrepancies [ 19 ]. Although the C max values in the different studies are different, the clearance of pimobendan in the current study is similar to previous reports [ 8 ].…”

Section: Discussionmentioning

confidence: 99%

Preliminary Bioequivalence of an Oral Pimobendan Solution Formulation with Reference Solution Formulation in Beagle Dogs

Saengklub

Boonyarattanasoonthorn

Kijtawornrat

et al. 2022

Veterinary Sciences

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Oral capsule and tablet formulations of pimobendan are widely used but may present difficulties for accurately dosing small patients. This study aimed to compare the pharmacokinetic (PK) characteristics, bioequivalence, and cardiovascular effects of a custom-made oral pimobendan solution (PS) formulation compared to a reference solution (RS) formulation in conscious, healthy dogs. A randomized crossover design was performed on dogs that received RS and PS formulations at a dose of 0.3 mg/kg. Blood samples were collected at 0, 0.083, 0.167, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 8, and 24 h after oral administration for PK analysis; bioequivalence was also calculated. Echocardiography was also performed to assess the cardiovascular effects. The results revealed that the plasma concentrations of pimobendan and o-desmethyl-pimobendan (active metabolite) in the case of both formulations were comparable. The relative ratios of geometric mean concentrations for all significant parameters of PK were within a range of 80–125%, indicating bioequivalence. In addition, both formulations increased cardiac contraction significantly when compared with the baseline, and no differences in cardiac contractility were detected between the formulations. The PS formulation can be used as alternative to the RS formulation for the management of congestive heart disease because of the bioequivalence between the two formulations.

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“…In vivo, pimobendan is rapidly metabolized in the liver to the more potent metabolite UDCG 212. 24,46,47 Investigating only the effect of pimobendan in our study may not accurately reflect the substances to which canine platelets in vivo are exposed. Therefore, investigating the effect of UDCG 212 on platelet aggregation using a mixture of pimobendan and UDCG 212 or, perhaps even more relevant, blood from dogs treated with pimobendan would be relevant and could likely result in different findings than reported in our study.…”

Section: Association Between Basal Platelet Aggregation Response and ...mentioning

confidence: 94%

No impact of polymorphism in the phosphodiesterase 5A gene in Cavalier King Charles Spaniels on pimobendan‐induced inhibition of platelet aggregation response

Reimann,

Faisst,

Knold

et al. 2023

Veterinary Internal Medicne

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BackgroundA variant in the canine phosphodiesterase (PDE) 5A gene (PDE5A:E90K) is associated with decreased concentrations of circulating cyclic guanosine monophosphate (cGMP) and response to PDE5 inhibitor treatment. Pimobendan is a PDE inhibitor recommended for medical treatment of certain stages of myxomatous mitral valve disease (MMVD) in dogs.HypothesisPDE5A:E90K polymorphism attenuates the inhibitory effect of pimobendan on in vitro platelet aggregation and increases basal platelet aggregation in Cavalier King Charles Spaniels (CKCS). Selected clinical variables (MMVD severity, sex, age, hematocrit, platelet count in platelet‐rich plasma [PRP], and echocardiographic left ventricular fractional shortening [LV FS]) will not show an association with results.AnimalsFifty‐two privately owned CKCS with no or preclinical MMVD.MethodsUsing blood samples, we prospectively assessed PDE5A genotype using Sanger sequencing and adenosine diphosphate‐induced platelet aggregation response (area under the curve [AUC], maximal aggregation [MaxA], and velocity [Vel]) with and without pimobendan using light transmission aggregometry. Dogs also underwent echocardiography.ResultsPimobendan inhibited platelet function as measured by AUC, MaxA, and Vel at a concentration of 10 μM (P < .0001) and Vel at 0.03 μM (P < .001). PDE5A:E90K polymorphism did not influence the inhibitory effect of pimobendan or basal platelet aggregation response.Conclusions and Clinical ImportanceThe PDE5A:E90K polymorphism did not influence in vitro basal platelet aggregation response or the inhibitory effect of pimobendan on platelet aggregation in CKCS. Dogs with the PDE5A:E90K polymorphism did not appear to have altered platelet function or response to pimobendan treatment.

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Pharmacokinetics of Pimobendan and Its Metabolite O-Desmethyl-Pimobendan Following Rectal Administration to Healthy Dogs

Cited by 8 publications

References 26 publications

Pharmacodynamics and Pharmacokinetics of Injectable Pimobendan and Its Metabolite, O-Desmethyl-Pimobendan, in Healthy Dogs

Pharmacodynamics and Pharmacokinetics of Injectable Pimobendan and Its Metabolite, O-Desmethyl-Pimobendan, in Healthy Dogs

Preliminary Bioequivalence of an Oral Pimobendan Solution Formulation with Reference Solution Formulation in Beagle Dogs

No impact of polymorphism in the phosphodiesterase 5A gene in Cavalier King Charles Spaniels on pimobendan‐induced inhibition of platelet aggregation response

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