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 Anesthesiology Section, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern CH-3001, Switzerland.

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Christoph Peterbauer Anesthesiology Section, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern CH-3001, Switzerland.

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M. Fabiana Landoni Pharmacology Department, Veterinary Faculty, La Plata University, La Plata 1900, Argentina.

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Olivier L. Levionnois Anesthesiology Section, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern CH-3001, Switzerland.

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Urs Schatzmann Anesthesiology Section, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern CH-3001, Switzerland.

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Claudia Spadavecchia Anesthesiology Section, Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Bern CH-3001, Switzerland.

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Wolfgang Thormann Department of Clinical Pharmacology, Faculty of Medicine, University of Bern, Bern CH-3010, Switzerland.

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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.

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