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Pharmacokinetics of single oral dose of Pimobendan in Hispaniolan Amazon parrots (Amazona ventralis).

Abstract: Pimobendan is a phosphodiesterase (PDE) inhibitor and calcium sensitizer with inotropic, lusitropic, and rasodilator properties used in the treatment of congestive heart failure. The mechanism of action is by inhibition of PDE III and V and by increasing intracellular calcium sensitivity in the cardiac myocardium. Pharmacokinetic and pharmacodynamic studies have been published in humans, dogs, and cats, but there are no studies in avian species. Pimobendan has been used in birds at the empirical dosage of 0.25 mg/kg q12h. To determine the pharmacokinetic parameters of pimobendan in Hispaniolan Amazon parrots (Amazona ventralis), 3 pilot studies with 2 birds, each receiving 1, 3, and 10 mg/kg PO, provided the basis for the pivotal trials with 6 birds, each receiving 10 mg/kg PO using 2 different suspensions. Blood samples were obtained at 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, and 18 hours after drug administration. Plasma concentrations were determined by liquid chromatography-tandem mass spectrometry (HPLC/MS) by use of electrospray ionization. Because of the erratic and low concentrations of pimobendan, pharmacokinetic parameters were calculated using naive averaged analysis. Plasma concentrations after commercial pimobendan tablet suspension at 10 mg/kg reached a Cmax of 8.26 ng/mL at 3 hours with a terminal half-life of 2.1 hours, while concentrations after the bulk chemical suspension reached a Cmax of 1.28 ng/mL at 12 hours and had a terminal half-life of 2.3 hours. Further studies evaluating the effect of oral pimobendan in parrots are needed.

Key words: pimobendan, pharmacokinetic, inotropic, psittacine, congestive heart failure, avian, Hispaniolan Amazon parrots, Amazona ventralis

Introduction

Cardiovascular disease occurs frequently in companion psittacine bids, and congestive heart failure frequently is a diagnosed cardiac disease. (1,2) In one retrospective study evaluating 107 companion psittacine birds submitted for necropsy, 36% had visible gross lesions of the heart and the major vessels, and 99% exhibited at least low-grade pathologic changes of the heart or major vessels on histologic examination. (1) In another postmortem retrospective study of 26 psittacine birds examined for the presence of cardiac disease, 5.6% of all birds examined had congestive heart failure. (2) Conventional therapy for congestive heart failure includes diuretics and angiotensin converting enzyme inhibitors, which are combined on occasion with a cardiac glycoside. Digoxin is the most commonly prescribed cardiac glycoside. It is a weak positive inotrope, and, therefore, mildly increases cardiac contractility. However, chronic use of cardiac glycosides has several limitations, including a low therapeutic index, difficulty in therapeutic drug monitoring, and the propensity to induce arrhythmias. This is heightened in avian species because of the lack of pharmacodynamic data, the necessity to compound most of the cardiac drugs, and the small size of the patients, which makes accurate dosing more difficult. New positive inotropic agents with higher safety margins and stronger effects on cardiac contractility have been introduced in human and veterinary cardiology during the last 20 years (3) and their use must be explored in the avian patient.

Pimobendan is a benzimidazole-pyridazone derivative and a novel cardiotonic vasodilator (inodilator). (4) This molecule belongs to the drug class of phosphodiesterase inhibitors and calcium sensitizers, along with adibendan, levosimendan, and saterinone. (4,5) Pimobendan effectively inhibits phosphodiesterase III, which reduces the breakdown of cyclic adenosine monophosphate (cAMP), thus having a positive inotropic effect through the mobilization of intracellular calcium. (4-8) However, the inotropic effect of pimobendan is due minimally to cAMP-triggered calcium accumulation and mainly the result of the calcium-sensitizing effect on the cardiac myofibrils. (4) The calcium-sensitizing effect of pimobendan is mediated by an increase of the affinity of troponin C calcium-binding sites to calcium, which in turn, lowers the threshold for calcium-dependent myofibril contraction. (5,7) Moreover, pimobendan acts as a phosphodiesterase V inhibitor, causing cAMP-mediated systemic, and pulmonary arterial and venous dilation. (3,4) Contrary to cardiac glycosides, and most intravenous and oral inotropes, pimobendan does not increase myocardial oxygen consumption. (9) Electrophysiologic effects of pimobendan are reduced atrial, atrioventricular nodal, and ventricular refractory periods, and enhanced atrioventricular conduction. (10) Pimobendan also downregulates proinflammatory cytokines and increases glucose-induced insulin release. (11,12) In summary, pimobendan acts as a positive inotrope (increase cardiac contractility), a positive lusitrope (improved ventricular relaxation), and a peripheral vasodilator.

The pharmacokinetics of pimobendan have been investigated in several species. In humans and dogs, oral bioavailability is close to 60% to 65%. (13,14) The drug is largely protein-bound (>90%) and peak plasma levels are observed within 1 to 4 hours. (13,14) In cats, oral bioavailability has not been determined, but maximum plasma concentrations are reached between 0.9 and 1.7 hours, and are four times that observed in dogs. (15) Pimobendan is approved for use in dogs at a dosage of 0.25 mg/kg every 12 hours. (13)

The objective of the current study was to evaluate the pharmacokinetics of oral pimobendan in Hispaniolan Amazon parrots (Amazona ventralis). The hypothesis was that oral administration of pimobendan, calculated based on dog and cat doses, would reach plasma concentrations in parrots between 5.2 and 7.9 ng/mL, which are considered therapeutic in humans. (16)

Materials and Methods

Animals

We used 14 adult Hispaniolan Amazon parrots of unknown sex in this study. The birds were part of the Louisiana State University School of Veterinary Medicine research colony. All parrots were considered healthy before and during the study as determined by physical examination. The mean weight [+ or -] SD of the parrots was 305 [+ or -] 19 g. For the duration of the study, the birds were housed in stainless steel cages (0.6 x 0.6 x 0.6 m) and maintained on a 12-hour light-to-dark cycle. A commercial pelleted diet was fed to all birds (Kaytee Exact Maintenance, Kaytee Products, Chilton, WI, USA), and fresh water was provided ad libitum. Food was removed in the morning before lights in the room were turned on. Food was returned after the 2-hour blood sample was taken. The Institutional Animal Care and Use Committee at the Louisiana State University approved the experimental protocol.

Experimental design

Pilot and first trial (tablets): Three pilot studies with 2 birds each were performed to determine an approximate dose that would reach detectable plasma concentrations. The pivotal trial then was performed in 6 additional birds. The data collected from 2 birds from the third pilot study were added to the data collected from the 6 additional birds from the pivotal trial for analysis. Pimobendan tablets (2.5 mg for the first 2 pilot studies, and 5 mg for the third pilot study and the trial, Vetmedin, Boehringer-Ingelheim, Saint Joseph, MO, USA) were crushed into a fine powder, and mixed with 1.2 and 2.5 mL, respectively, of a suspending vehicle (Ora-Plus, Paddock Laboratories Inc, Minneapolis, MN, USA) by using 2 Luer Lock, 10-mL syringes connected to a 3-way stopcock. With the added volume of the powder, the resulting suspension concentration was 0.7 and 1.2 mg/mL, respectively. The suspensions were prepared a maximum of 1 hour before administration. For each pilot study, the birds were restrained manually and dosed at 1 mg/kg (2 birds), 3 mg/kg (2 birds), and 10 mg/kg (2 birds) into the crop with a syringe and a metallic feeding tube. The metallic feeding tube was then flushed into the crop with 3 mL of water. For the pivotal study, the 10 mg/kg dose was used. Blood samples (0.3 mL each) were obtained at 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, and 18 hours from the jugular or the brachial veins and placed in lithium-heparin tubes (Microtainer, Becton Dickinson and Company, Franklin Lakes, NJ, USA) on ice. Plasma was separated and stored at -80 [degrees]C in a cryovial. At completion of the study, butorphanol tartrate (3 mg/kg IM once, Torbugesic, Fort Dodge Animal Health, Fort Dodge, 1A, USA) and lactated Ringer's solution (20 mL/kg SC once) were administered to each bird.

Second trial (bulk chemical): Bulk chemical (99% pimobendan, Ontario Chemicals Inc, Guelph, Ontario, Canada) was purchased and mixed with Ora-Plus to obtain a concentration of 5 mg/mL. The suspension was stirred continuously by using a magnetic mixer and a stir bar immersed in the suspension. Six different birds were selected for this second trial. Each bird was restrained manually, and dosed with 10 mg/kg of the suspension orally into the crop using a syringe and a metallic feeding tube. The feeding tube was then flushed with 1.5 mL of water. Blood samples (0.3 mL each) were obtained at 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, and 18 hours after dosing from the jugular or brachial veins and placed in lithium-heparin tubes on ice. Plasma was separated and stored at -80[degrees]C in a cryovial until analysis. At completion of the study, birds were treated with butorphanol and lactated Ringer's solution at the doses listed above.

Measurement of plasma concentrations: Sample preparation for analysis consisted of adding 300 [micro]L of acetonitrile containing 100 ng/mL amoxapine (100%, Sigma-Aldrich, St Louis, MO, USA), which served as the internal standard, to 100 [micro]L of parrot plasma in a 96-well, 1-mL protein precipitation filter plate (Thermo Scientific, Waltham, MA, USA). The samples were mixed for 5 minutes by using a microplate genie (Scientific Industries, Bohemia, NY, USA) and then placed on a vacuum manifold (Porvair Sciences, Leatherhead, UK). Samples were filtered into a 96-well receiving plate (Agilent Technologies, Santa Clara, CA, USA). The filtrate was dried under nitrogen and 150 [micro]L of 0.1% formic acid in water: 0.1% formic acid in acetonitrile (2:98, vol/vol) was added and the residue dissolved by mixing for 5 minutes (Microplate genie, Scientific Industries). Samples were injected for analysis directly from the receiving plate. The injection volume was 15 [micro]L. Plasma standard curves were prepared by adding pimobendan to untreated, pooled parrot plasma for concentrations from 1 to 50 ng/mL (5 concentration points); therefore, the analytical range was 1 to 50 ng/mL.

Analyses were conducted by using a Thermo Open Autosampler (Thermo Fisher Scientific, San Jose, CA, USA) and a Thermo Accela pumping system interfaced to a Thermo Velos linear ion trap-ion trap system equipped with a heated electrospray ionization (HESI) probe and operated in the positive ion mode. Chromatographic separation was achieved on a 3.5-pm particle size, 2.1 X 100 mm (i.d.) 600 bar Agilent ZORBAX Eclipse XDB C18 rapid resolution HT threaded column with an Alltech Direct-Connect Column 2 [micro]m pre-filter (Alltech, Deerfield, IL, USA) using gradient elution. The following gradient system was used as the mobile phase: mobile phase A (0.1% formic acid in H20) and a mobile phase B (0.1% formic acid in acetonitrile) delivered at a constant flow rate of 0.3 mL/min throughout the analysis; A:B 98:2 (0-2 minutes), 25:75 (3 minutes), 2:98 (4-6 minutes), 98:2 (7 minutes), 98:2 (13 minutes), allowing for reequilibration. The tandem mass spectrometry (MS/MS) analysis was performed by using selected reaction monitoring (SRM) of the protonated molecular ions for the analytes, and scanning the targeted ions and fragment ions in a single segment. The heated ESI source temperature was 300[degrees] C, sheath gas pressure was 25 psi, auxiliary gas pressure was 7 psi, spray voltage (kV) was 5, capillary temperature was 275[degrees] C, and S-lens RF level was 35%. The collision pressure was 1.5 psi of high purity argon. Data for the molecular ions used to generate diagnostic fragment ions were amoxapine-molecular ion (M+1) 314.3 m/z, fragment ions 245, 271, 297 m/z, and pimobendan-molecular ion (M+1) 335.3, fragment ions 224, 250, 263, and 292 m/z.

Detection data were collected and integration of chromatographic peaks was performed by Xcalibur 2.0.7 (Thermo Fisher Scientific) LCquan 2.5.6 QF 30115 software. Identification of the compounds was based on the presence of the molecular ion at the correct retention time ([+ or -] 1%), the presence of at least 3 transition ions, and the correct ratio of these ions to one another ([+ or -] 25% relative).

The concentration of compounds in plasma samples was determined from the ratio of the peak area of the target analyte to that of the internal standard (amoxapine), by reference to calibration curves prepared by spiking blank plasma samples with pimobendan (1-50 ng/mL) plus a consistent amount of internal standard (100 ng/mL). The transition ion used for quantitation of pimobendan was m/z 250 and for amoxapine it was m/z 271. Inter- and intraassay variation also were determined as were the limit of detection (LOD; concentration response greater than 3 times baseline noise) and limit of quantification (LOQ; concentration giving a percent relative standard deviation of less than 15% and a percent bias of less than 10% of known values based on serial dilutions and standard curves) for pimobendan.

To examine matrix effects, responses were calculated for standard curves generated from fortifying 4 preextracted and subsequently spiked parrot (Amazona species) plasma samples and 4 spiked, unextracted water samples. The slopes of individual parrot plasma samples were compared to each other and the percent relative standard deviation (RSD) was determined. The mean of these slopes also was compared to the mean of spiked water curves and the %RSD was calculated for pimobendan.

Pharmacokinetic analyses: Pharmacokinetic analysis was performed with computer software (WinNonlin 5.2, Pharsight Corporation, Mountain View, CA, USA). Because of the erratic and low concentrations of pimobendan, pharmacokinetic analyses were performed on average plasma concentrations at each time point for each route of administration. If the plasma concentration was less than the analytical limit of quantification, a value of 0 was used to determine the mean and standard deviation at that time point. The calculated noncompartmental parameters included the area under the curve from 0 to infinity (AUC) calculated by the linear trapezoidal method, percent of the AUC extrapolated to infinity (AUC extrapolated), the plasma clearance per fraction of the dose absorbed (Cl/F), terminal half-life (T 1/2 [lambda]z), terminal rate constant ([lambda]z), mean residence time from 0 to infinity (MRT), and volume of distribution (area method) per fraction of the dose absorbed (Vz/F). The maximum plasma concentration (Cmax) and time to maximum plasma concentration (Tmax) were determined directly from the mean plasma concentrations.

Results

The analytical method was highly specific, with no interferences being evident in Amazon parrot plasma or method blanks for the analysis of pimobendan and the internal standard amoxapine. The two compounds were well separated (pimobendan, 4.0 minutes; amoxapine, 4.2 minutes) temporally and by mass. The calculated LOD for pimobendan was 0.04 ng/mL. The LOQ was calculated as 0.11 ng/mL. The proven analytical range was 1 to 50 ng/mL as determined from the standard curve; therefore, only plasma concentrations within this range were used for data analyses. Linearity of fortified standard curves (n = 6) was greater than or equal to [r.sup.2] = 0.99. Inter- and intraassay variabilities were less than 15% (n = 5). Using a simple protein precipitation protocol, recovery of pimobendan was near quantitative over the range of concentrations examined (1-50 ng/mL, 79-93%). No matrix effects (less than 10% RSD) were observed for individual plasma samples or for pooled plasma samples over the range of concentrations examined when slopes of standard curves (prepared as described) were compared.

Pilot and first trial (tablets): Plasma concentrations were below the limit of quantification at all time points after administration of 1 mg/kg. The mean plasma concentrations after dosing at 3 mg/ kg as part of the pilot study are included in Figure 1, but due to the small number of samples above 1 ng/mL, pharmacokinetic analysis was not conducted on this dose. Plasma concentrations after oral administration of pimobendan tablet suspension at 10 mg/kg are presented in Figures 1 and 2. The calculated pharmacokinetic parameters are presented in Table 1.

Second trial (powder): Plasma concentrations after oral administration of 10 mg/kg of pimobendan powder suspension are presented in Figures 1 and 3. The calculated pharmacokinetic parameters of oral pimobendan powder in Flispaniolan Amazon parrots are presented in Table 1.

Parrot behavior was normal throughout the trials, and no adverse effects were detected.

Discussion

To our knowledge, this is the first report on the pharmacokinetics of pimobendan in avian species. Pimobendan plasma concentrations, Cmax, and AUC were higher after administration of a suspension compounded from the tablet compared with a suspension compounded from the raw powder. These data suggest that pimobendan should be compounded from the tablet to achieve a larger amount of the absorbed drug. In some countries, compounding from bulk (powder) when a commercial formulation is available might be against regulations. One possible reason for the tablet to result in larger absorption is that it contains the citric acid excipient. Unless the pimobendan oral formulation contains the citric acid excipient to control the pH of the formulation, oral absorption is poor. (17) The curves shown in the patent comparing oral absorption in dogs of the citric acid formulation and plain pimobendan appear similar to the observations of this study in birds. (17) The mean terminal half-life was 2.3 hours for the pimobendan powder suspension and 2.1 hours for the pimobendan tablet suspension. The terminal half-life of pimobendan is similar to that reported in healthy humans (2.56-2.86 hours), (18) dogs (pimobendan and the active metabolite were, respectively, 0.5 and 2 hours),13 and cats (1.5 hours). (15)

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

The AUC for pimobendan tablet suspension was 49.1 h * ng/mL, similar to that reported in humans (52.9-53.7 h * ng/mL), (18) while the AUC for the pimobendan powder was much lower at 14.63 h*ng/mL. The Cmax for pimobendan tablet suspension was > 6 times higher than the Cmax for pimobendan powder suspension (8.26 and 1.28 ng/mL, respectively) and was observed at 3 and 12 hours, respectively, indicating a slower and lower absorption of the pimobendan powder suspension. In humans, Cmax for pimobendan enantiomers were 15.8 and 16.8 ng/mL at 1.23 and 1.24 hours after administration of 7.5 mg PO. (18) In dogs, Cmax of pimobendan and the active metabolite were 3.09 and 3.66 ng/mL, respectively, after oral administration of 0.25 mg/kg of pimobendan. (13) Individual dog Cmax values for pimobendan and the active metabolite were observed 1 to 4 hours, respectively, after dosing. (13) In cats, Cmax ranged between 11.1 and 59.4 ng/mL, and was predicted between 0.9 and 1.7 hours, respectively, after receiving 0.23 to 0.35 mg/kg of pimobendan. (15)

[FIGURE 3 OMITTED]

The PO Vz/F for pimobendan tablet suspension was 605 L/kg, whereas the Yz/F for pimobendan powder suspension was 2220 L/kg in Hispaniolan Amazon parrots. The large values are most likely influenced by a low fraction of the drug being absorbed (bioavailability). The true volume of distribution was not calculated because an IV formulation of pimobenden is not available for injection and IV dosing is needed to calculate the Vz. The oral bioavailability was not determined directly in the current study because an IV crossover study was required, but it appears to be much lower than that reported in humans (0.51) and dogs (0.55), and likely to be associated with the substantially higher doses needed in parrots to reach similar plasma concentrations. (18) Whether the apparent low bioavailability is a result of incomplete drug absorption or extensive first pass metabolism is unclear, because pimobendan metabolites were not assessed due to lack of pimobendan metabolite reference standards. Further studies must assess the metabolism and metabolite profile of pimobendan in parrots. This is especially important because an active metabolite, desmethyl-pimobendan, has been identified in other species.

The estimated effect-site concentrations corresponding with 50% of the maximal effect in humans receiving 5 mg PO were 6.54 [+ or -] 1.35 and 6.64 [+ or -] 1.35 ng/mL in a simultaneous pharmacokinetic-pharmacodynamic model. (16) In dogs, there was a delay between peak blood levels of pimobendan and active metabolite, and the maximum physiologic response (peak LV dP/dtmax). (13) Blood levels of pimobendan and active metabolite began to drop before maximum contractility was seen. (13) The therapeutic effect of pimobendan tablet or powder suspension at 10 mg/kg PO is unknown. Additional studies using integrated pharmacokinetic-pharmacodynamic (PK-PD) models for pimobendan may be able to determine the relationship between plasma concentrations and the cardiovascular effects in parrots.

The pharmacokinetic method approach used was naive average analysis from multiple parrots, and was necessary because of the erratic and low plasma concentrations of pimobendan. This methodology does not allow measurement of variability in the calculated pharmacokinetic parameters, because pooled concentrations are analyzed as though derived from a single bird. (19) Despite the lack of an objective measurement of variability between of the pharmacokinetic parameters, we believe that the variability was high based on the plasma concentrations presented in Figures 2 and 3.

The dose of 10 mg/kg selected for this study was based on the results of the 3 pilot studies in 6 birds. This 10 mg/kg dose is much higher (approximately 40 times) than that used in humans or in dogs or cats; however, it resulted in similar plasma pimobendan concentrations as those seen in these species. However the active metabolite was not measured in this study, which if produced in parrots, would be expected to contribute to desired and adverse effects. The primary adverse effects that have been observed in dogs are gastrointestinal disorders. (20) Overall, the pharmacokinetic profile obtained in this species may be difficult to extrapolate to other species, especially since the drug undergoes significant hepatic biotransformation and metabolism. It is noteworthy that a Harris' hawk (Parabuteo unicinctus) diagnosed and treated for congestive heart failure at the LSU-Veterinary Teaching Hospital with 10 mg/kg of oral pimobendan exhibited plasma concentration several hundred times higher than observed here (peak, 25 196 ng/mL; trough, 716 ng/mL) (H. Beaufrere, August 2012). This illustrates the difficulties to extrapolate one dosage from one taxon to another. There is some evidence that pimobendan may increase the development of arrhythmias. (20) Atrial fibrillation or increased ventricular ectopic beats have been reported in dogs on pimobendan, but because cardiomyopathy can cause arrhythmias, a causative effect has not been fully established. In a field trial (56 day) performed in dogs, (13) the adverse effect incidence (at least one occurrence reported per dog) was poor appetite (38%), lethargy (33%), diarrhea (30%), dyspnea (29%), azotemia (14%), weakness and ataxia (13%), pleural effusion (10%), syncope (9%), cough (7%), sudden death (6%), ascites (6%), and heart murmur (3%). In a study comparing cardiac adverse effects of pimobendan with benazepril, (21) dogs with mitral valve regurgitation had increases in systolic function but also developed worsening mitral valve disease, specifically mitral valve lesions (acute hemorrhages, endocardial papilloform hyperplasia on the dorsal surfaces of the leaflets, and infiltration of chordae tendinae by glycosaminoglycans) not seen in the benazepril group. No adverse effects were observed in the birds during the study although this study did not include an objective quantification and the cardiovascular system was not monitored. A Harris' hawk and an eclectus parrot (Eclectus roratus) treated with 10 mg/kg for several months did not exhibit any observable adverse effects. Therefore, additional studies are needed before the routine use of pimobendan in avian patients.

In Hispaniolan Amazon parrots dosed one time orally, pimobendan tablet suspension administered at 10 mg/kg appears to achieve plasma concentrations that would be associated with desired therapeutic effects, whereas pimobendan powder suspension administered at the same dose did not achieve similar plasma concentrations. Safety and efficacy of pimobendan treatment regimens in Hispaniolan Amazon parrots requires further investigation to determine its potential use for the treatment of cardiovascular disease in psittacine birds.

Acknowledgments: We thank Valerie Wiebe, Pharm D, at the University of California Davis School of Veterinary Medicine, for her help with this project; and Dr Romain Pariaut at Louisiana State University School of Veterinary Medicine for reviewing the manuscript.

References

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David Sanchez-Migallon Guzman, LV, MS, Dipl ECZM (Avian), Dipl ACZM, Hugues Beaufrere, Dr MedVet, Dipl ECZM (Avian), Butch KuKanich, DVM, PhD, Dipl ACVCP, Steven A. Barker, PhD, Joao Brandao, LMV, Joanne Paul-Murphy, DVM, Dipl ACZM, and Thomas N. Tully Jr, DVM, MS, Dipl ABVP (Avian), Dipl ECZM (Avian)

From the Department of Veterinary Medicine and Epidemiology, School of Veterinary Medicine, University of California, One Shields Ave, Davis, CA 95616, USA (Guzman, Paul-Murphy); Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Skip Bertman Dr, Baton Rouge, LA 70803, USA (Beaufrere, Brandao, Tully); Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, KS 66506, USA (KuKanich); and the Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA (Barker).
Table 1. Pharmacokinetic parameters of pimobendan
suspension administered to Hispaniolan Amazon
parrots after a single oral dose of 10 mg/kg made
from powder (n = 6) or tablets (n = 8) using naive
averaged noncompartmental analysis.
U.S. Total
                                      Dose

Parameter          Units       Powder      Tablet

AUC extrapolated   %               4.5        2.9
AUC                h * ng/mL      14.63      49.1
Cl/F               mL/min/kg   11384       3396
Cmax               ng/mL           1.28       8.26
T 1/2 [lambda]z    h               2.3        2.1
[lambda]z          1/h             0.301      0.336
MRT                h              10.0        4.5
Tmax               h              12          3
Vz/F               L/kg         2220        605
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Title Annotation:Original Studies
Author:Guzman, David Sanchez-Migallon; Beaufrere, Hugues; KuKanich, Butch; Barker, Steven A.; Brandao, Joao
Publication:Journal of Avian Medicine and Surgery
Article Type:Report
Date:Jun 1, 2014
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