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

Jiwoong Her,Randolph L Winter,Lenore M Bacek,Dawn M Boothe,Crisanta Cruz-Espindola,Kendon W Kuo

doi:10.3389/fvets.2020.00423

Abstract

Objective: This study describes the pharmacokinetics of parent pimobendan (PIM) and its active metabolite, o-desmethyl-pimobendan (ODMP), after oral and rectal administration of pimobendan to healthy dogs.Animals: A total of eight healthy privately owned dogs were used in this study.Procedures: The dogs received a single dose (0.5 mg/kg) of a commercially available pimobendan tablet per os (PO). Twelve blood samples were collected over a 12-h period for pharmacokinetic analysis. After a 24-h washout period, the dogs received the same dose of pimobendan solution per rectum (PR), and samples were obtained at the same time for analysis.Results: For PIM, PO vs. PR, respectively, the mean maximum plasma concentration (Cmax, ng/ml) was 49.1 ± 28.7 vs. 10.1 ± 2, the time to reach a maximum concentration (Tmax, h) was 2.1 ± 0.9 vs. 1 ± 0.4, the disappearance half-life (t1/2, h) was 1.8 ± 0.8 vs. 2.2 ± 0.6, and the area under the concentration–time curve (AUC, ng*h/ml) was 148.4 ± 71.6 vs. 31.1 ± 11.9, with relative bioavailability (F, %) of 25 ± 8. For ODMP, PO vs. PR, respectively, Cmax was 30.9 ± 10.4 vs. 8.8 ± 4.8, Tmax was 3.2 ± 1.6 vs. 1.7 ± 1.1, and t1/2 was 5.0 ± 2.7 vs. 8.3 ± 4.8, with AUC of 167.8 ± 36.2 vs. 50.1 ± 19.2 and F of 28 ± 6. The differences between PO and PR were significant (P < 0.03) for AUC and Cmax for both PIM and ODMP.Conclusions and Clinical Relevance: The pharmacokinetics of PIM and ODMP were described following PO and PR administration. The findings suggest that pimobendan PR might achieve effective concentrations and, as such, warrant future studies of clinical effectiveness in treating dogs with congestive heart failure and which are unable to receive medication PO.

Highlights

Pimobendan, a benzimidazole-pyridazinone derivative, is known as an inodilator that possesses the unique combination of a positive inotrope and a vasodilator [1]
This study describes the pharmacokinetics of parent pimobendan (PIM) and its active metabolite, o-desmethyl-pimobendan (ODMP), after oral and rectal administration of pimobendan to healthy dogs
The findings suggest that pimobendan per rectum (PR) might achieve effective concentrations and, as such, warrant future studies of clinical effectiveness in treating dogs with congestive heart failure and which are unable to receive medication per os (PO)

Summary

Introduction

Pimobendan, a benzimidazole-pyridazinone derivative, is known as an inodilator that possesses the unique combination of a positive inotrope and a vasodilator [1]. It acts as a positive inotrope by sensitizing the affinity of calcium for binding to troponin C on cardiac myocytes and inhibiting phosphodiesterase 3 (PDE3). Pimobendan improves the cardiac output without increasing the myocardial oxygen consumption [1,2,3] This unique combination of properties makes pimobendan desirable in the treatment of congestive heart failure (CHF) secondary to myxomatous mitral valve disease or dilated cardiomyopathy in dogs [2,3,4,5]. The American College of Veterinary Internal Medicine (ACVIM) Specialty of Cardiology recommends pimobendan use for acute, hospital-based therapy of patients with current clinical signs of CHF as well as for patients with advanced myxomatous mitral valve disease prior to the onset of CHF (ACVIM heart disease stages B2, C, and D) [4]

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Discussion

Conclusion