Pharmacokinetics and cardiovascular effects following a single oral administration of a nonaqueous pimobendan solution in healthy dogs

Abstract

Pimobendan is an inodilator used in the treatment of canine congestive heart failure (CHF). The aim of this study was to investigate the pharmacokinetics and cardiovascular effects of a nonaqueous oral solution of pimobendan using a single-dose, operator-blinded, parallel-dose study design. Eight healthy dogs were divided into two treatment groups consisting of water (negative control) and pimobendan solution. Plasma samples and noninvasive measures of cardiovascular function were obtained over a 24-h period following dosing. Pimobendan and its active metabolite were quantified using an ultra-high-performance liquid chromatography-mass spectrometer (UHPLC-MS) assay. The oral pimobendan solution was rapidly absorbed [time taken to reach maximum concentration (Tmax ) 1.1 h] and readily converted to the active metabolite (metabolite Tmax 1.3 h). The elimination half-life was short for both pimobendan and its active metabolite (0.9 and 1.6 h, respectively). Maximal cardiovascular effects occurred at 2-4 h after a single oral dose, with measurable effects occurring primarily in echocardiographic indices of systolic function. Significant effects persisted for <8 h. The pimobendan nonaqueous oral solution was well tolerated by study dogs.

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

“…However, the therapeutic efficacy of the plasma concentrations reported in our study is difficult to interpret, partly because the plasma concentrations associated with the presumed efficacy of PIM and OMDP are not clearly defined in dogs. The authors noticed a disparity among the pharmacokinetic profiles of pimobendan reported by others (1,6,21). The key pharmacokinetic parameters of PIM and ODMP from different studies are summarized in Table 2.…”

“…While the oral bioavailability of the commercial tablet is 70% (1,2,6), oral administration is not a viable route in an emergency situation. Many dogs presenting with advanced stage of CHF are in severe respiratory distress on presentation.…”

Pimobendan: Contexto Histórico E Aplicação Clínica Em Cães

“…O pimobendan é um composto orgânico, derivado de benzimidazolepiridazinona, classificado como fármaco inodilatador, por apresentar características inotrópicas e vasodilatadoras (EPOCH STUDY GROUP, 2002;POLLESELLO et al, 2016;YATA et al;).…”

“…O pimobendan é um fármaco inodilatador, derivado de benzimidazolepiridazinona, que apresenta duplo mecanismo de ação, aumentando a sensibilização do cálcio intracelular, proporcionando aumento na contratilidade miocárdica e efeito vasodilatador por meio da inibição da fosfodiesterase 3 (PDE3) (YATA et al, 2016;GORDON et al, 2017).…”

“…A biodisponibilidade esperada está compreendida entre 60 a 65%, contudo, apresenta diminuição quando administrado junto a alimento. Foi constatado que quando administrado o pimobendan em cães, na dose de 1 mg/kg a cada 12 horas, por um período de 27 dias, este não produz taquifilaxia e tampouco foram observados efeitos acumulativos que aumentem o inotropismo de forma acentuada (BELL et al, 2016;YATA et al, 2016). Com o tempo de eliminação plasmática inferior a 30 minutos e meia-vida de aproximadamente duas horas com efeitos farmacodinâmicos persistindo por mais de oito horas (BELL et al, 2016;YATA et al, 2016).…”