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

Gerald Beddies Dr med vet1, Philip R. Fox DVM, MS2, Mark D. Papich DVM, MS3, Venkata-Rangaro Kanikanti PhD4, Ralph Krebber Dr rer nat5, and Bruce W. Keene DVM, MS6
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  • 1 Research & Development—Clinical Research & Development, Animal Health Division, Bayer HealthCare AG, 51368 Leverkusen, Germany
  • | 2 The Animal Medical Center, Caspary Institute, 510 E 62nd St, New York, NY 10065
  • | 3 Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606
  • | 4 Research & Development—Clinical Research & Development, Animal Health Division, Bayer HealthCare AG, 51368 Leverkusen, Germany
  • | 5 Research & Development, Bayer Crop Science AG, 40789 Monheim, Germany
  • | 6 Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC 27606

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.

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.