Journal article
Oral Coadministration of Fluconazole with Tramadol Markedly Increases Plasma and Urine Concentrations of Tramadol and the O- Desmethyltramadol Metabolite in Healthy Dogs
Drug metabolism and disposition, Vol.47(1), pp.15-25
01/2019
Handle:
https://hdl.handle.net/2376/103517
PMCID: PMC6290082
PMID: 30366901
Abstract
Tramadol is used frequently in the management of mild to moderate pain conditions in dogs. This use is controversial because multiple reports in treated dogs demonstrate very low plasma concentrations of
-desmethyltramadol (M1), the active metabolite. The objective of this study was to identify a drug that could be coadministered with tramadol to increase plasma M1 concentrations, thereby enhancing analgesic efficacy. In vitro studies were initially conducted to identify a compound that inhibited tramadol metabolism to
-desmethyltramadol (M2) and M1 metabolism to
,
-didesmethyltramadol (M5) without reducing tramadol metabolism to M1. A randomized crossover drug-drug interaction study was then conducted by administering this inhibitor or placebo with tramadol to 12 dogs. Blood and urine samples were collected to measure tramadol, tramadol metabolites, and inhibitor concentrations. After screening 86 compounds, fluconazole was the only drug found to inhibit M2 and M5 formation potently without reducing M1 formation. Four hours after tramadol administration to fluconazole-treated dogs, there were marked statistically significant (
< 0.001; Wilcoxon signed-rank test) increases in plasma tramadol (31-fold higher) and M1 (39-fold higher) concentrations when compared with placebo-treated dogs. Conversely, plasma M2 and M5 concentrations were significantly lower (11-fold and 3-fold, respectively;
< 0.01) in fluconazole-treated dogs. Metabolite concentrations in urine followed a similar pattern. This is the first study to demonstrate a potentially beneficial drug-drug interaction in dogs through enhancing plasma tramadol and M1 concentrations. Future studies are needed to determine whether adding fluconazole can enhance the analgesic efficacy of tramadol in healthy dogs and clinical patients experiencing pain.
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Details
- Title
- Oral Coadministration of Fluconazole with Tramadol Markedly Increases Plasma and Urine Concentrations of Tramadol and the O- Desmethyltramadol Metabolite in Healthy Dogs
- Creators
- Tania E Perez Jimenez - Program in Individualized Medicine, Pharmacogenomics Laboratory, Department of Veterinary Clinical Sciences, Washington State University College of Veterinary Medicine, Pullman, Washington (T.E.P.J., K.L.M., T.L.G., S.A.G., M.H.C.); and Department of Anatomy and Physiology, Institute of Computational Comparative Medicine, Kansas State University College of Veterinary Medicine, Manhattan, Kansas (B.K., H.J.) teperezjimenez@wsu.eduButch Kukanich - Program in Individualized Medicine, Pharmacogenomics Laboratory, Department of Veterinary Clinical Sciences, Washington State University College of Veterinary Medicine, Pullman, Washington (T.E.P.J., K.L.M., T.L.G., S.A.G., M.H.C.); and Department of Anatomy and Physiology, Institute of Computational Comparative Medicine, Kansas State University College of Veterinary Medicine, Manhattan, Kansas (B.K., H.J.)Hyun Joo - Program in Individualized Medicine, Pharmacogenomics Laboratory, Department of Veterinary Clinical Sciences, Washington State University College of Veterinary Medicine, Pullman, Washington (T.E.P.J., K.L.M., T.L.G., S.A.G., M.H.C.); and Department of Anatomy and Physiology, Institute of Computational Comparative Medicine, Kansas State University College of Veterinary Medicine, Manhattan, Kansas (B.K., H.J.)Katrina L Mealey - Program in Individualized Medicine, Pharmacogenomics Laboratory, Department of Veterinary Clinical Sciences, Washington State University College of Veterinary Medicine, Pullman, Washington (T.E.P.J., K.L.M., T.L.G., S.A.G., M.H.C.); and Department of Anatomy and Physiology, Institute of Computational Comparative Medicine, Kansas State University College of Veterinary Medicine, Manhattan, Kansas (B.K., H.J.)Tamara L Grubb - Program in Individualized Medicine, Pharmacogenomics Laboratory, Department of Veterinary Clinical Sciences, Washington State University College of Veterinary Medicine, Pullman, Washington (T.E.P.J., K.L.M., T.L.G., S.A.G., M.H.C.); and Department of Anatomy and Physiology, Institute of Computational Comparative Medicine, Kansas State University College of Veterinary Medicine, Manhattan, Kansas (B.K., H.J.)Stephen A Greene - Program in Individualized Medicine, Pharmacogenomics Laboratory, Department of Veterinary Clinical Sciences, Washington State University College of Veterinary Medicine, Pullman, Washington (T.E.P.J., K.L.M., T.L.G., S.A.G., M.H.C.); and Department of Anatomy and Physiology, Institute of Computational Comparative Medicine, Kansas State University College of Veterinary Medicine, Manhattan, Kansas (B.K., H.J.)Michael H Court - Program in Individualized Medicine, Pharmacogenomics Laboratory, Department of Veterinary Clinical Sciences, Washington State University College of Veterinary Medicine, Pullman, Washington (T.E.P.J., K.L.M., T.L.G., S.A.G., M.H.C.); and Department of Anatomy and Physiology, Institute of Computational Comparative Medicine, Kansas State University College of Veterinary Medicine, Manhattan, Kansas (B.K., H.J.)
- Publication Details
- Drug metabolism and disposition, Vol.47(1), pp.15-25
- Academic Unit
- Veterinary Clinical Sciences, Department of
- Publisher
- United States
- Grant note
- R01 GM102130 / NIGMS NIH HHS
- Identifiers
- 99900546672701842
- Language
- English
- Resource Type
- Journal article