• View in gallery
    Figure 1—

    Concentration-time profiles for bisoprolol following oral administration of a 1 mg/kg dose in each of 6 healthy dogs. The assessment at time 0 hours was performed immediately before administration of the drug.

  • View in gallery
    Figure 2—

    Concentration-time profiles for carvedilol following oral administration of a 1 mg/kg dose in each of 6 healthy dogs. The assessment at time 0 hours was performed immediately before administration of the drug. Concentrations were less than the limit of quantitation of the assay after 6 hours.

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    Bristow MR. β-Adrenergic receptor blockade in chronic heart failure. Circulation 2000;101:558569.

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    Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the International Society for Heart and Lung Transplantation; endorsed by the Heart Failure Society of America. Circulation 2001;104:29963007.

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    Bristow MR, Abraham WT, Yoshikawa T, et al. Second- and third-generation beta-blocking drugs in chronic heart failure. Cardiovasc Drugs Ther 1997;11 (suppl 1):291296.

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    Gilbert EM, Abraham WT, Olsen S, et al. Comparative hemo-dynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart. Circulation 1996;94:28172825.

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    The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II). A randomized trial. Lancet 1999;353:913.

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    Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation 2002;106:21942199.

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    Kukin ML, Kalman J, Charney RH, et al. Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure. Circulation 1999;99:26452651.

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    • Export Citation
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    Arsenault WG, Boothe DM, Gordon SG, et al. Pharmacokinetics of carvedilol after intravenous and oral administration in conscious healthy dogs. Am J Vet Res 2005;66:21722176.

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    Sawangkoon S, Miyamoto M, Nakayama T, et al. Acute cardiovascular effects and pharmacokinetics of carvedilol in healthy dogs. Am J Vet Res 2000;61:5760.

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    Brodde OE. Bisoprolol (EMD 33512) a highly selective beta-1 adrenoceptor antagonist: in vitro and in vivo studies. J Cardiovasc Pharmacol 1986;8 (suppl 11):S29S35.

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    Eichhorn EJ, Bristow MR. The carvedilol prospective randomized cumulative survival (COPERNICUS) trial. Curr Control Trials Cardiovasc Med 2001;2:2023.

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    Strein K, Sponer G, Muller-Beckmann B, et al. Pharmacological profile of carvedilol, a compound with beta-blocking and vasodilating properties. J Cardiovasc Pharmacol 1987;10 (suppl 11):S33S41.

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Comparison of the pharmacokinetic properties of bisoprolol and carvedilol in healthy dogs

Gerald BeddiesResearch & Development—Clinical Research & Development, Animal Health Division, Bayer HealthCare AG, 51368 Leverkusen, Germany

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Philip R. FoxThe Animal Medical Center, Caspary Institute, 510 E 62nd St, New York, NY 10065

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Mark D. PapichDepartment of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606

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Venkata-Rangaro KanikantiResearch & Development—Clinical Research & Development, Animal Health Division, Bayer HealthCare AG, 51368 Leverkusen, Germany

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Ralph KrebberResearch & Development, Bayer Crop Science AG, 40789 Monheim, Germany

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Bruce W. KeeneDepartment of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606

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Abstract

Objective—To compare the pharmacokinetic properties and bioavailability following oral and IV administration of bisoprolol, a second-generation β1-adrenoceptor–selective blocking agent, with those of carvedilol, a third-generation β12 and α1-adrenoceptor blocking agent, in dogs.

Animals—12 healthy adult Beagles.

Procedures—A prospective, parallel group study was performed. The dogs were allocated to 1 of 2 groups (6 dogs/group) and were administered orally a 1 mg/kg dose of either bisoprolol or carvedilol. Following a 1-week washout period, each cohort received a 1 mg/kg dose of the same drug IV. Blood samples were collected before and after drug administration, and serum concentrations, pharmacokinetic variables, and bioavailability for each agent were assessed.

Results—After oral administration of bisoprolol, the geometric mean value of the area under the concentration-time curve extrapolated to infinity (AUCinf) was 2,195 μg/L (coefficient of variation [CV], 15%). After IV administration of bisoprolol, the dose-normalized geometric mean AUCinf was 2,402 μg/L (CV, 19%). Oral bioavailability of bisoprolol was 91.4%. After oral administration of carvedilol, the geometric mean AUCinf was 70 μg/L (CV, 81%). After IV administration of carvedilol, the geometric mean AUCinf was 491 μg/L (CV, 23%). Oral bioavailability of carvedilol was 14.3%. Total body clearance was low (0.42 L/h/kg) for bisoprolol and high (2.0 L/h/kg) for carvedilol.

Conclusions and Clinical Relevance—After oral administration, carvedilol underwent extensive first-pass metabolism and had limited bioavailability; bisoprolol had less first-pass effect and higher bioavailability. Collectively, these differences suggested that, in dogs, bisoprolol has less interindividual pharmacokinetic variability, compared with carvedilol.

Abstract

Objective—To compare the pharmacokinetic properties and bioavailability following oral and IV administration of bisoprolol, a second-generation β1-adrenoceptor–selective blocking agent, with those of carvedilol, a third-generation β12 and α1-adrenoceptor blocking agent, in dogs.

Animals—12 healthy adult Beagles.

Procedures—A prospective, parallel group study was performed. The dogs were allocated to 1 of 2 groups (6 dogs/group) and were administered orally a 1 mg/kg dose of either bisoprolol or carvedilol. Following a 1-week washout period, each cohort received a 1 mg/kg dose of the same drug IV. Blood samples were collected before and after drug administration, and serum concentrations, pharmacokinetic variables, and bioavailability for each agent were assessed.

Results—After oral administration of bisoprolol, the geometric mean value of the area under the concentration-time curve extrapolated to infinity (AUCinf) was 2,195 μg/L (coefficient of variation [CV], 15%). After IV administration of bisoprolol, the dose-normalized geometric mean AUCinf was 2,402 μg/L (CV, 19%). Oral bioavailability of bisoprolol was 91.4%. After oral administration of carvedilol, the geometric mean AUCinf was 70 μg/L (CV, 81%). After IV administration of carvedilol, the geometric mean AUCinf was 491 μg/L (CV, 23%). Oral bioavailability of carvedilol was 14.3%. Total body clearance was low (0.42 L/h/kg) for bisoprolol and high (2.0 L/h/kg) for carvedilol.

Conclusions and Clinical Relevance—After oral administration, carvedilol underwent extensive first-pass metabolism and had limited bioavailability; bisoprolol had less first-pass effect and higher bioavailability. Collectively, these differences suggested that, in dogs, bisoprolol has less interindividual pharmacokinetic variability, compared with carvedilol.

Chronic β1-adrenoceptor signaling is considered to be a critical cardiotoxic pathway in a failing heart.1 Randomized clinical trials have revealed potential benefits of the use of β-adrenoceptor blockers in management strategies for humans with heart failure.2 Beneficial effects of second- and third-generation β-adrenoceptor blockers include improved systolic function, prevention of worsening systolic function, and reduced remodeling.1,3,4 Both β1-adrenoceptor–selective agents and third-generation pan-adrenoceptor blocking compounds are effective in prolonging survival in humans with chronic heart failure.1,5,6 Limited data suggest that third-generation compounds may have more beneficial effects on left ventricular function1,3,4; however, other researchers have detected no difference between second- and third-generation compounds.7 There has been increasing interest in the use of β-adrenoceptor blockers in management strategies for heart failure associated with naturally occurring myxomatous valve degeneration in dogs.8,9

Bisoprolol is a β1-adrenoceptor–selective blocker that has a low affinity for β2-adrenoceptors in bronchial smooth muscle, blood vessels, and fat cells and no intrinsic sympathomimetic activity.10,11 In humans, approximately 50% of a dose of bisoprolol is metabolized by the liver, and approximately 50% is excreted as unchanged drug. A similar balanced clearance of bisoprolol occurs in dogs (60% of a dose is metabolized by the liver, and 40% is excreted as unchanged drug),12 which distinguishes bisoprolol from lipophilic β-adrenoceptor blockers such as carvedilol and metoprolol and from hydrophilic β-adrenoceptor blockers such as atenolol. Treatment with bisoprolol significantly prolongs survival time in humans with heart failure.5 Carvedilol is a third-generation pan-adrenoceptor blocker with α1-adrenoceptor blocking activity as well as potent anti-oxidant effects. Treatment with carvedilol also prolongs survival time in humans with heart failure.6,13–15

In addition to their mechanisms of action, other factors contribute to the potential safety and efficacy of drugs, including pharmacokinetic differences in bioavailability, drug metabolism, plasma protein binding, volume of distribution, and elimination.16 The objective of the study reported here was to compare the pharmacokinetic properties and bioavailability of bisoprolol following oral and IV administration with those of carvedilol in dogs.

Materials and Methods

Dogs—A prospective study that had a parallel group design was performed. Twelve adult, male, purpose-bred Beagles were allocated to 1 of 2 cohorts (6 dogs/group). Each group was to receive treatment with either carvedilol or bisoprolol. All of the dogs were maintained according to governmental humane treatment guidelines17 at the Animal Center of Bayer Health-Care AG in Germany. All dogs were considered healthy on the basis of physical examination findings, were regularly vaccinated, and had not been treated with either bisoprolol or carvedilol for at least 2 weeks prior to the study. The dogs were fed a commercially available dry dog food once daily in the morning except on drug administration days, when they were fed approximately 4 hours following treatment. Tap water from the municipal water supply was provided ad libitum for the duration of the study.

Experimental procedures—Each cohort was first treated orally with bisoprolol or carvedilol. Following a 1-week washout period, each group was treated IV with a bolus injection of the same compound. For the oral treatments, the active ingredienta of bisoprolol hemifumarate or mortar-ground carvedilol tabletsb were prepared in identical gelatin capsules and administered at a dose of 1 mg/kg. For the IV treatments, sterile solutions of each drug were prepared specially for the study and administered via indwelling cephalic venous catheters at a dose of 1 mg/kg.

During the oral treatment phase, blood samples (approx 4 mL each) were collected via jugular venipuncture with a commercially available serum collection systemc immediately before (time 0 hours) and at 15, 30, 45, 60, and 90 minutes and 2, 4, 6, 8, 12, 16, and 24 hours after treatment. During the IV treatment phase, blood samples (approx 4 mL each) were collected in a similar manner before (time 0 hours) and at 3, 6, 15, 30, 45, 60, and 90 minutes and 2, 4, 6, 8, 12, 16, and 24 hours after treatment.

Serum was obtained from each blood sample via centrifugation (1,800 × g for 10 minutes at 4°C). Bisoprolol or carvedilol concentration in each sample was analyzed by use of a validated high-performance liquid chromatography procedure with detection via tandem mass spectrometry methods. The concentration of the known active metabolite (M4) of bisoprolol was also measured via this technique. Whereas the concentrations of bisoprolol and M4 were analyzed by tandem mass spectrometry following protein precipitation from the serum samples, determination of carvedilol concentration was performed via direct injection of serum into a turbulent flow chromatography–tandem mass spectrometry system.18

Pharmacokinetic calculations—Pharmacokinetic calculations were performed by use of commercially available pharmacokinetic software.d The serum concentrations measured at each of the time points after oral or IV administration of each dose were considered as 1 data set. Relevant pharmacokinetic variables (ie, Cmax, Tmax, AUCinf, AUCinf-DN, Cl, Cl/F, VD, VDss, MRT, and serum half-life) were calculated by use of noncompartmental analysis for extravascular input (oral drug administration) or IV bolus input (IV drug administration). Data were uniformly weighted, and the linear-logarithmic trapezoidal rule was used to calculate the AUC. Variables were logarithmically transformed as needed for statistical calculations. Datum points used for serum half-life determination were chosen manually by selecting as many points as possible during the apparent terminal elimination phase on the pharmacokinetic (logarithm-concentration vs time) graphs. Datum points associated with any rapid decrease in concentration after Cmax was reached and datum points occurring after the limit of quantitation of the assay was reached were not used. Bioavailability (ie, F) was calculated from the geometric mean group values of AUCinf (AUCinf-DN for bisoprolol) by use of an equation as follows:

article image

Analysis of the IV bisoprolol solution revealed that it did not contain the labeled amount of bisoprolol concentration. Consequently, it became necessary to perform a dose-normalization analysis of serum bisoprolol concentrations following IV administration. Results of this analysis were not available before the blood samples were collected. For all analyses, a value of P < 0.05 was considered significant.

Results

The dogs in the 2 treatment groups were not different with respect to mean ± SD values of weight (carvedilol group, 11.5 ± 1.0 kg and bisoprolol group, 10.4 ± 1.1 kg; P = 0.117) or age (carvedilol group, 12.6 ± 2 months and bisoprolol group, 12.5 ± 1.1 months; P = 0.972). Oral and IV administrations of both drugs (1 mg/kg doses) were clinically tolerated well by all dogs. Oral administration of bisoprolol resulted in similar concentration-time profiles in all dogs (Figure 1). Oral absorption of bisoprolol was rapid, Cmax and Tmax varied only slightly, and the distribution and elimination phases were similar in all dogs.

Figure 1—
Figure 1—

Concentration-time profiles for bisoprolol following oral administration of a 1 mg/kg dose in each of 6 healthy dogs. The assessment at time 0 hours was performed immediately before administration of the drug.

Citation: American Journal of Veterinary Research 69, 12; 10.2460/ajvr.69.12.1659

Pharmacokinetic variables for bisoprolol following IV and oral treatments were calculated (Table 1). Concentrations of an active metabolite of bisoprolol (M4) were also measured. This metabolite was considered of minor pharmacokinetic importance; at maximum, the AUC of M4 was less than the AUC of unchanged bisoprolol by a factor of approximately 10.

Table 1—

Values of pharmacokinetic variables following IV or oral administration of bisoprolol (1 mg/kg) in 6 healthy dogs.

VariableIV administrationOral administration
Mean ± SDMedianGeometric meanCV of the geometric mean (%)Mean ± SDMedianGeometric meanCV of the geometric mean (%)
Cmax (μg/L)408 ± 7538940218322 ± 26130631818
Tmax (h)NANANANA1.1 ± 0.71137
Half-life (h)3.9 ± 0.33.83.984 ± 3.53.8414
AUCinf (h•μg/L)2,228 ± 4072,1882,197182,217 ± 1,8832,1082,19515
AUCinf-DN (h•μg/L)2,438 ± 4712,4062,40219NANANANA
VD (L/kg)2.4 ± 0.62.32.425NANANANA
Cl (L/h/kg)0.42 ± 0.080.420.4219NANANANA
CI/F(L/h/kg)NANANANA0.46 ± 0.360.480.4615
MRT (h)6 ± 0.35.964NANANANA
VDss (L/kg)2.5 ± 0.52.52.520NANANANA

CV = Coefficient of variation. NA = Not applicable.

Following IV administration of bisoprolol, the geometric mean Cl was 0.42 L/h/kg and values of VD and VDss were comparable. The geometric mean AUCinf-DN was 2,402 h•μg/L after IV treatment with bisoprolol, and Cmax was 402 μg/L.

Following oral administration of bisoprolol, the geometric mean Cl was 0.46 L/h/kg; the geometric mean AUCinf was 2,195 h•μg/L. Thus, the bioavailability of bisoprolol following oral treatment was 91.4% (ranging from 84.5% to 108.4% among individual dogs). The Cmax (318 μg/L) was achieved approximately 1 hour after oral administration of bisoprolol in all dogs, indicating rapid and uniform absorption via the oral administration route.

After both IV and oral administration of bisoprolol, the geometric mean elimination half-life was approximately 4 hours, and the MRT of the bisoprolol molecules within the body was calculated to be 6 hours. Via both routes of administration, the inter-individual variability in bisoprolol Cmax was 18%, and the interindividual variability in bioavailability (ie, AUC) was 15% to 19%.

In contrast, oral administration of carvedilol resulted in variable concentration-time profiles, with wide individual variation (Figure 2). One dog had substantially higher Cmax and AUC than the other 5 dogs. Absorption, as well as Cmax, also varied considerably among the dogs following carvedilol administration.

Figure 2—
Figure 2—

Concentration-time profiles for carvedilol following oral administration of a 1 mg/kg dose in each of 6 healthy dogs. The assessment at time 0 hours was performed immediately before administration of the drug. Concentrations were less than the limit of quantitation of the assay after 6 hours.

Citation: American Journal of Veterinary Research 69, 12; 10.2460/ajvr.69.12.1659

The geometric mean Cl following IV administration of carvedilol was 2.0 L/h/kg (Table 2). The geometric mean AUCinf was 491 h•μg/L and Cmax was 738 μg/L after IV administration of carvedilol.

Table 2—

Values of pharmacokinetic variables following IV or oral administration of carvedilol (1 mg/kg) in 6 healthy dogs.

VariableIV administrationOral administration
Mean ± SDMedianGeometric meanCV of the geometric mean (%)Mean ± SDMedianGeometric meanCV of the geometric mean (%)
Cmax (μg/L)788 ± 3486707383951 ± 42384089
Tmax (h)NANANANA1.1 ± 0.71.10.994
Half-life (h)1 ± 0.20.91161.2 ± 0.51.11.152
AUCinf (h•ng/L)501 ± 1045384912387 ± 69667081
VD (L/kg)2.9 ± 0.62.92.920NANANANA
Cl(L/h/kg)2.1 ± 0.51.8223NANANANA
CI/F (L/h/kg)NANANANA17.3 ± 10.415.214.481
MRT (h)1.3 ± 0.31.31.322NANANANA
VDss (17kg)2.7 ± 0.62.82.722NANANANA

See Table 1 for key.

Following oral administration of carvedilol, the geometric mean Cl was 14.4 L/h/kg (Table 2). The apparent geometric mean VDss (2.7 L/kg) was only slightly lower than the VD calculated after IV administration of the single bolus (2.9 L/kg). Such large differences between oral and IV Cl rates in the face of comparable VD values were consistent with substantial first-pass hepatic metabolism. Following oral administration of carvedilol, Cmax was achieved at a median of 1.1 hours, and the geometric mean Cmax was 40 μg/L, indicating rapid absorption of carvedilol. The geometric mean AUCinf was 70 h•μg/L after oral treatment, resulting in an oral bioavailability for carvedilol of 14.3% (ranging from 5.4% to 36.7% in individual dogs).

The geometric mean elimination half-life for carvedilol was approximately 1 hour following both IV and oral administrations. The MRT of the carvedilol molecules within the body was calculated to be 1.3 hours. Following oral administration of carvedilol, the inter-individual variability of the geometric mean Cmax was 89%, and the geometric mean interindividual variability of AUCinf was 81%; both values were much higher than the respective geometric mean interindividual variabilities of Cmax and AUCinf following IV administration (39% and 23%, respectively).

Discussion

In the dogs of the present study, bisoprolol was rapidly and completely absorbed following oral administration, and Cmax and AUC values were similar after IV and oral administrations. The oral bioavailability of bisoprolol was 91.4%, which indicated that it undergoes little first-pass hepatic metabolism. Interindividual variability in either Cmax or AUC was minimal (18% and 15%, respectively). These results suggest that bisoprolol administration should provide predictable and consistent blood concentrations in dogs that might benefit clinically from β-adrenoceptor blockade.

Carvedilol was absorbed almost as rapidly as bisoprolol. Because carvedilol is lipophilic,19 relatively complete absorption of the drug via the oral route of administration would be expected in dogs. The large differences in Cmax and AUC between the IV and oral treatments with carvedilol likely represent substantial first-pass hepatic metabolism after oral administration, which is consistent with high systemic clearance. Accordingly, carvedilol would be expected to be highly affected by changes in hepatic blood flow. The bioavailability of carvedilol in the dogs of the present study was 14.3%, slightly lower than values in dogs that have been reported previously.8 Moreover, following carvedilol administration, large interindividual variability in the concentration-time profiles, Cmax, and AUC was recorded. This large interindividual variability is also probably attributable to extensive but variable first-pass hepatic metabolism.

These pharmacokinetic results, when considered together with the low and variable oral bioavailability, suggest that carvedilol administration may result in less predictable plasma concentrations, compared with bisoprolol administration; thus, carvedilol dosing schemes may be subsequently less reliable. These findings are not entirely surprising considering the results of previously published studies8,9,11,12,20 involving bisoprolol and carvedilol. For example, following oral bisoprolol administration in a variety of species (rats, mice, guinea pigs, hamsters, rabbits, dogs, and monkeys), bisoprolol is almost completely absorbed. In contrast to the physicochemical properties of bisoprolol, carvedilol is lipophilic and undergoes extensive hepatic metabolism. Hepatic metabolism of carvedilol is known to result in different metabolite profiles in different animal species (eg, dogs, humans, rats, and mice).19,20 In fact, carvedilol is not recommended for humans with severe hepatic impairment.21 In humans, 2 metabolites of carvedilol (M4 and M5) are known to be pharmacodynamically active; they are equipotent to the unchanged compound with respect to β-adrenoceptor blockade, but possess only approximately 33% of the potency of unchanged carvedilol with respect to α1-adrenoceptor–mediated vasodilation.19 The antioxidant effects of carvedilol appear to depend largely on the M14 metabolite, which was reported to have superior antioxidant activity, compared with that of unchanged carvedilol.22 In contrast to humans, none of the active carvedilol metabolites (M2, M4, M5, and M14) that are believed to contribute to the potential therapeutic efficacy of the drug19 have been found in relevant circulating quantities in the plasma of dogs at 1, 3, and 6 hours after administration.20 Biliary secretion appears to be the predominant pathway for the excretion of carvedilol in dogs.20 The potential impact of these interspecies pharmacokinetic differences on the efficacy of carvedilol in dogs is presently unknown.

In the present study, the pharmacodynamics of either bisoprolol or carvedilol were not assessed. Moreover, the therapeutic efficacy of either compound for any potential clinical indication was not investigated. Nevertheless, we did determine that bisoprolol had superior pharmacokinetic properties in dogs, compared with carvedilol. Following oral administration in dogs, carvedilol underwent extensive first-pass metabolism and was poorly and variably bioavailable. In contrast, bisoprolol was highly and reliably bioavailable; in the dogs of our study, there was little interindividual variation in the absorption, peak plasma concentration, or clearance of the drug.

ABBREVIATIONS

AUC

Area under the concentration-time curve

AUCinf

Area under the concentration-time curve extrapolated to infinity from the last time point

AUCinf-DN

Dose-normalized area under the concentration-time curve extrapolated to infinity from the last time point

Cl

Total body clearance

Cl/F

Total body clearance of the fraction of drug absorbed

Cmax

Maximum drug concentration

MRT

Mean residence time

Tmax

Time to reach maximum drug concentration

VD

Apparent volume of distribution in the terminal phase

VDss

Apparent volume of distribution at steady state

a.

Merck & Cie KG, Altdorf, Switzerland.

b.

Dilatrend, 6.25-mg tablet, Roche, Grenzach-Whylen, Germany.

c.

Serum monovette, Sarstedt AG Co, Nümbrecht, Germany.

d.

WinNonlin Professional, Pharsight Corp, Mountain View, Calif.

References

  • 1.

    Bristow MR. β-Adrenergic receptor blockade in chronic heart failure. Circulation 2000;101:558569.

  • 2.

    Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1995 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the International Society for Heart and Lung Transplantation; endorsed by the Heart Failure Society of America. Circulation 2001;104:29963007.

    • Search Google Scholar
    • Export Citation
  • 3.

    Bristow MR, Abraham WT, Yoshikawa T, et al. Second- and third-generation beta-blocking drugs in chronic heart failure. Cardiovasc Drugs Ther 1997;11 (suppl 1):291296.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Gilbert EM, Abraham WT, Olsen S, et al. Comparative hemo-dynamic, left ventricular functional, and antiadrenergic effects of chronic treatment with metoprolol versus carvedilol in the failing heart. Circulation 1996;94:28172825.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II). A randomized trial. Lancet 1999;353:913.

  • 6.

    Packer M, Fowler MB, Roecker EB, et al. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation 2002;106:21942199.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Kukin ML, Kalman J, Charney RH, et al. Prospective, randomized comparison of effect of long-term treatment with metoprolol or carvedilol on symptoms, exercise, ejection fraction, and oxidative stress in heart failure. Circulation 1999;99:26452651.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Arsenault WG, Boothe DM, Gordon SG, et al. Pharmacokinetics of carvedilol after intravenous and oral administration in conscious healthy dogs. Am J Vet Res 2005;66:21722176.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Sawangkoon S, Miyamoto M, Nakayama T, et al. Acute cardiovascular effects and pharmacokinetics of carvedilol in healthy dogs. Am J Vet Res 2000;61:5760.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 10.

    Harting J, Becker KH, Bergmann R, et al. Pharmacodynamic profile of the beta 1-adrenoceptor antagonist bisoprolol. Arzneimittelforschung 1986;36:200208.

    • Search Google Scholar
    • Export Citation
  • 11.

    Brodde OE. Bisoprolol (EMD 33512) a highly selective beta-1 adrenoceptor antagonist: in vitro and in vivo studies. J Cardiovasc Pharmacol 1986;8 (suppl 11):S29S35.

    • Search Google Scholar
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Contributor Notes

Dr. Beddies' present address is Animal Health Division, Bayer Health-Care AG, 12809 Shawnee Mission Pkwy, Shawnee, KS 66216.

Presented in abstract form at the American College of Veterinary Internal Medicine Symposium, Seattle, June 2007.

Address correspondence to Dr. Keene.