Dissertation
IMPROVING THE EFFECTIVENESS OF TRAMADOL IN DOGS THROUGH UNDERSTANDING CYP METABOLISM
Doctor of Philosophy (PhD), Washington State University
01/2017
Handle:
https://hdl.handle.net/2376/111350
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, while pharmacokinetic studies demonstrated relatively low circulating concentrations of O-desmethyltramadol (M1). Analgesia has been attributed to the opioid effects of M1, while tramadol and the other major metabolites (N-desmethyltramadol, M2 and N,O didesmethyltramadol, M5) are considered inactive at opioid receptors. The aims of this study were to identify the CYPs responsible for M1, M2 and M5 formation in canine liver, identify through an in vitro screening approach a drug that could potentially inhibit M2 and M5 formation without affecting M1 formation, and confirm through an in vivo study the inhibition of M2 and M5 and the increase of M1. Recombinant canine CYP activities indicated that M1 and M5 from M2 were formed by CYP2D15, M2 was largely formed by CYP2B11 and CYP3A12; M5 from M1 was formed by CYP2C21 and CYP2B11. This was confirmed by dog liver microsomes studies that showed selective inhibition of M1 and M5 from M2 formation by quinidine, M2 formation by chloramphenicol and CYP2B11 antiserum, M5 formation from M1 by sulphaphenazole and chloramphenicol and induction of M2 and M5 formation from M1 by phenobarbital. In vitro inhibition studies were developed to identify a compound that would inhibit the formation of M2 and M5 without affecting M1 formation. In a randomized cross over drug interaction study, racemic tramadol was administered with or without (placebo) fluconazole to 12 dogs. Temperature and pressure nociceptive thresholds were also measured to evaluate analgesic efficacy. After screening 86 compounds, only one (fluconazole) was capable of inhibiting M2 and M5 formation while minimally affecting M1 formation. Four hours after tramadol administration to fluconazole-treated dogs, there were statistically significant increases in plasma tramadol (31-fold higher) and M1 (39-fold higher) concentrations when compared to placebo-treated dogs. Conversely, plasma concentrations of M2 and M5 were significantly lower (11-fold and 3-fold, respectively) in the treated dogs. The metabolite concentrations in urine followed a similar trend. There were no significant differences in temperature and pressure nociceptive thresholds between treatments.
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Details
- Title
- IMPROVING THE EFFECTIVENESS OF TRAMADOL IN DOGS THROUGH UNDERSTANDING CYP METABOLISM
- Creators
- Tania Elena Perez Jimenez
- Contributors
- Michael H Court (Advisor)Katrina L Mealey (Committee Member)Tamara L Grubb (Committee Member)Stephen A Greene (Committee Member)
- Awarding Institution
- Washington State University
- Academic Unit
- College of Veterinary Medicine
- Theses and Dissertations
- Doctor of Philosophy (PhD), Washington State University
- Number of pages
- 133
- Identifiers
- 99900581512901842
- Language
- English
- Resource Type
- Dissertation