Metabolism, pharmacokinetics and selected pharmacodynamic effects of codeine following a single oral administration to horses

Sophie R Gretler; Carrie J Finno; Daniel S McKemie; Philip H Kass; Heather K Knych

doi:10.1016/j.vaa.2020.04.004

Metabolism, pharmacokinetics and selected pharmacodynamic effects of codeine following a single oral administration to horses

Vet Anaesth Analg. 2020 Sep;47(5):694-704. doi: 10.1016/j.vaa.2020.04.004. Epub 2020 Apr 23.

Authors

Sophie R Gretler¹, Carrie J Finno², Daniel S McKemie¹, Philip H Kass², Heather K Knych³

Affiliations

¹ K.L. Maddy Equine Analytical Pharmacology Laboratory, University of California-Davis, School of Veterinary Medicine, Davis, CA, USA.
² Department of Population Health and Reproduction, School of Veterinary Medicine, University of California, Davis, CA, USA.
³ K.L. Maddy Equine Analytical Pharmacology Laboratory, University of California-Davis, School of Veterinary Medicine, Davis, CA, USA; Department of Veterinary Molecular Biosciences, School of Veterinary Medicine, University of California, Davis, CA, USA. Electronic address: hkknych@ucdavis.edu.

Abstract

Objective: To describe the pharmacokinetics and selected pharmacodynamic variables of codeine and its metabolites in Thoroughbred horses following a single oral administration.

Study design: Prospective experimental study.

Animals: A total of 12 Thoroughbred horses, nine geldings and three mares, aged 4-8 years.

Methods: Horses were administered codeine (0.6 mg kg^-1) orally and blood was collected before administration and at various times until 120 hours post administration. Plasma and urine samples were collected and analyzed for codeine and its metabolites by liquid chromatography-mass spectrometry, and plasma pharmacokinetics were determined. Heart rate and rhythm, step counts, packed cell volume and total plasma protein were measured before and 4 hours after administration.

Results: Codeine was rapidly converted to the metabolites norcodeine, codeine-6-glucuronide (C6G), morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Plasma codeine concentrations were best represented using a two-compartment model. The C_max, t_max and elimination t_½ were 270.7 ± 136.0 ng mL^-1, 0.438 ± 0.156 hours and 2.00 ± 0.534 hours, respectively. M3G was the main metabolite detected (C_max 492.7 ± 35.5 ng mL^-1), followed by C6G (C_max 96.1 ± 33.8 ng mL^-1) and M6G (C_max 22.3 ± 4.96 ng mL^-1). Morphine and norcodeine were the least abundant metabolites with C_max of 3.17 ± 0.95 and 1.42 ± 0.79 ng mL^-1, respectively. No significant adverse or excitatory effects were observed.

Conclusions and clinical relevance: Following oral administration, codeine is rapidly metabolized to morphine, M3G, M6G, C6G and norcodeine in horses. Plasma concentrations of M6G, a presumed active metabolite of morphine, were comparable to concentrations reported previously following administration of an analgesic dose of morphine to horses. Codeine was well tolerated based on pharmacodynamic variables and behavioral observations.

Keywords: codeine; horse; metabolism; pharmacodynamics; pharmacokinetics.

MeSH terms

Administration, Oral
Animals
Area Under Curve
Codeine / blood
Codeine / metabolism
Codeine / pharmacokinetics*
Codeine / urine
Drug Administration Schedule
Female
Half-Life
Horses / metabolism*
Male

Substances

Codeine

Grants and funding

L40 TR001136/TR/NCATS NIH HHS/United States