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Research ArticleArticle

Tramadol Metabolism to O-Desmethyl Tramadol (M1) and N-Desmethyl Tramadol (M2) by Dog Liver Microsomes: Species Comparison and Identification of Responsible Canine Cytochrome P450s

Tania E. Perez, Katrina L. Mealey, Tamara L. Grubb, Stephen A. Greene and Michael H. Court
Drug Metabolism and Disposition December 2016, 44 (12) 1963-1972; DOI: https://doi.org/10.1124/dmd.116.071902
Tania E. Perez
Program in Individualized Medicine, Pharmacogenomics Laboratory, Department of Veterinary Clinical Sciences, Washington State University College of Veterinary Medicine, Pullman, Washington
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  • ORCID record for Tania E. Perez
Katrina L. Mealey
Program in Individualized Medicine, Pharmacogenomics Laboratory, Department of Veterinary Clinical Sciences, Washington State University College of Veterinary Medicine, Pullman, Washington
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Tamara L. Grubb
Program in Individualized Medicine, Pharmacogenomics Laboratory, Department of Veterinary Clinical Sciences, Washington State University College of Veterinary Medicine, Pullman, Washington
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Stephen A. Greene
Program in Individualized Medicine, Pharmacogenomics Laboratory, Department of Veterinary Clinical Sciences, Washington State University College of Veterinary Medicine, Pullman, Washington
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Michael H. Court
Program in Individualized Medicine, Pharmacogenomics Laboratory, Department of Veterinary Clinical Sciences, Washington State University College of Veterinary Medicine, Pullman, Washington
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This article has a correction. Please see:

  • Correction to “Tramadol Metabolism to O-Desmethyl Tramadol (M1) and N-Desmethyl Tramadol (M2) by Dog Liver Microsomes: Species Comparison and Identification of Responsible Canine Cytochrome P450s” - July 01, 2017

Abstract

Tramadol is widely used to manage mild to moderately painful conditions in dogs. However, this use is controversial, since clinical efficacy studies in dogs showed conflicting results, whereas pharmacokinetic studies demonstrated relatively low circulating concentrations of O-desmethyltramadol (M1). Analgesia has been attributed to the opioid effects of M1, whereas tramadol and the other major metabolite (N-desmethyltramadol, M2) are considered inactive at opioid receptors. This study aimed to determine whether cytochrome P450 (P450)–dependent M1 formation by dog liver microsomes is slower compared with cat and human liver microsomes and to identify the P450s responsible for M1 and M2 formation in canine liver. Since tramadol is used as a racemic mixture of (+)- and (−)-stereoisomers, both (+)-tramadol and (−)-tramadol were evaluated as substrates. M1 formation from tramadol by liver microsomes from dogs was slower than from cats (3.9-fold) but faster than humans (7-fold). However, M2 formation by liver microsomes from dogs was faster than those from cats (4.8-fold) and humans (19-fold). Recombinant canine P450 activities indicated that M1 was formed by CYP2D15, whereas M2 was largely formed by CYP2B11 and CYP3A12. This was confirmed by dog liver microsome studies that showed selective inhibition of M1 formation by quinidine and M2 formation by chloramphenicol and CYP2B11 antiserum, as well as induction of M2 formation by phenobarbital. Findings were similar for both (+)-tramadol and (−)-tramadol. In conclusion, low circulating M1 concentrations in dogs are explained in part by low M1 formation and high M2 formation, which is mediated by CYP2D15 and CYP2B11/CYP3A12, respectively.

Footnotes

    • Received June 3, 2016.
    • Accepted October 5, 2016.
  • This research was supported by the Morris Animal Foundation [Fellowship Training Grant D16CA-401 (to T.E.P.)], the National Institutes of Health National Institute of General Medical Sciences [Grant R-01-GM102130 (to M.H.C.)], and the William R. Jones Endowment to Washington State University College of Veterinary Medicine.

  • dx.doi.org/10.1124/dmd.116.071902.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 44 (12)
Drug Metabolism and Disposition
Vol. 44, Issue 12
1 Dec 2016
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Research ArticleArticle

Tramadol Metabolism in Dogs

Tania E. Perez, Katrina L. Mealey, Tamara L. Grubb, Stephen A. Greene and Michael H. Court
Drug Metabolism and Disposition December 1, 2016, 44 (12) 1963-1972; DOI: https://doi.org/10.1124/dmd.116.071902

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Research ArticleArticle

Tramadol Metabolism in Dogs

Tania E. Perez, Katrina L. Mealey, Tamara L. Grubb, Stephen A. Greene and Michael H. Court
Drug Metabolism and Disposition December 1, 2016, 44 (12) 1963-1972; DOI: https://doi.org/10.1124/dmd.116.071902
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