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Stereoselective pharmacokinetics of ketamine and norketamine after constant rate infusion of a subanesthetic dose of racemic ketamine or S-ketamine in Shetland ponies

M. Paula Larenza DVM, Dr med vet1, Christoph Peterbauer DVM, Dr med vet2, M. Fabiana Landoni DVM, PhD3, Olivier L. Levionnois DVM, Dr med vet4, Urs Schatzmann DVM, Dr med vet, PhD5, Claudia Spadavecchia DVM, Dr med vet, PhD6, and Wolfgang Thormann PhD7
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  • 1 Anesthesiology Section, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern CH-3001, Switzerland.
  • | 2 Anesthesiology Section, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern CH-3001, Switzerland.
  • | 3 Pharmacology Department, Veterinary Faculty, La Plata University, La Plata 1900, Argentina.
  • | 4 Anesthesiology Section, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern CH-3001, Switzerland.
  • | 5 Anesthesiology Section, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern CH-3001, Switzerland.
  • | 6 Anesthesiology Section, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern CH-3001, Switzerland.
  • | 7 Department of Clinical Pharmacology, Faculty of Medicine, University of Bern, Bern CH-3010, Switzerland.

Abstract

Objective—To evaluate pharmacokinetics of ketamine and norketamine enantiomers after constant rate infusion (CRI) of a subanesthetic dose of racemic ketamine or S-ketamine in ponies.

Animals—Five 6-year-old Shetland pony geldings that weighed between 101 and 152 kg.

Procedures—In a crossover study, each pony received a CRI of racemic ketamine (loading dose, 0.6 mg/kg; CRI, 0.02 mg/kg/min) and S-ketamine (loading dose, 0.3 mg/kg; CRI, 0.01 mg/kg/min), with a 1-month interval between treatments. Arterial blood samples were collected before and at 5, 15, 30, 45, and 60 minutes during drug administration and at 5, 10, 30, and 60 minutes after discontinuing the CRI. Plasma ketamine and norketamine enantiomers were quantified by use of capillary electrophoresis. Individual R-ketamine and S-ketamine concentration-versus-time curves were analyzed by use of a monocompartmental model. Plasma disposition curves for R-norketamine and S-norketamine were described by estimating the area under the concentration-versus-time curve (AUC), maximum concentration (Cmax), and time until Cmax.

Results—Plasma concentrations of S-ketamine decreased and biodegradation products increased more rapidly after S-ketamine CRI, compared with results after racemic ketamine CRI. The R-norketamine was eliminated faster than was the S-norketamine. Significant differences between treatments were found for the AUC of S-ketamine and within the racemic ketamine CRI for the AUC and Cmax of norketamine isomers.

Conclusions and Clinical Relevance—CRI of S-ketamine may be preferable over CRI of racemic ketamine in standing equids because the S-enantiomer was eliminated faster when infused alone instead of as part of a racemic mixture.

Abstract

Objective—To evaluate pharmacokinetics of ketamine and norketamine enantiomers after constant rate infusion (CRI) of a subanesthetic dose of racemic ketamine or S-ketamine in ponies.

Animals—Five 6-year-old Shetland pony geldings that weighed between 101 and 152 kg.

Procedures—In a crossover study, each pony received a CRI of racemic ketamine (loading dose, 0.6 mg/kg; CRI, 0.02 mg/kg/min) and S-ketamine (loading dose, 0.3 mg/kg; CRI, 0.01 mg/kg/min), with a 1-month interval between treatments. Arterial blood samples were collected before and at 5, 15, 30, 45, and 60 minutes during drug administration and at 5, 10, 30, and 60 minutes after discontinuing the CRI. Plasma ketamine and norketamine enantiomers were quantified by use of capillary electrophoresis. Individual R-ketamine and S-ketamine concentration-versus-time curves were analyzed by use of a monocompartmental model. Plasma disposition curves for R-norketamine and S-norketamine were described by estimating the area under the concentration-versus-time curve (AUC), maximum concentration (Cmax), and time until Cmax.

Results—Plasma concentrations of S-ketamine decreased and biodegradation products increased more rapidly after S-ketamine CRI, compared with results after racemic ketamine CRI. The R-norketamine was eliminated faster than was the S-norketamine. Significant differences between treatments were found for the AUC of S-ketamine and within the racemic ketamine CRI for the AUC and Cmax of norketamine isomers.

Conclusions and Clinical Relevance—CRI of S-ketamine may be preferable over CRI of racemic ketamine in standing equids because the S-enantiomer was eliminated faster when infused alone instead of as part of a racemic mixture.

Contributor Notes

Dr. Larenza's present address is Department of Clinical Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104.

Dr. Peterbauer's present address is Department for Small Animals and Horses, Clinic of Anaesthesiology and Perioperative Intensive Care, University of Veterinary Medicine, Vienna A-1210, Austria.

Supported by grants from the Vetsuisse Faculty of the University of Bern, Switzerland, and the Swiss National Science Foundation; and supported by Dr. E. Graeub AG.

Presented in part at the Association of Veterinary Anesthetists Spring Meeting, Paris, March 2005.

The authors thank Dr. M. Knobloch and R. Theurillat for assistance with the capillary electrophoresis analysis.

Address correspondence to Dr. Larenza.