Parent-Metabolite Pharmacokinetic Models for Tramadol – Tests of Assumptions and Predictions

Authors

Sam Holford, University of Auckland
Karel Allegaert, University Hospitals Leuven, Belgium
Brian J. Anderson, University of Auckland
Butch Kukanich, Kansas State University
Altamir B. Sousa, University of São Paulo
Amir Steinman, Hebrew University of Jerusalem
Bruno Pypendop, University of California
Reza Mehvar, Chapman UniversityFollow
Mario Giorgi, University of Pisa
Nick Holford, University of Auckland

Document Type

Article

Publication Date

2014

Abstract

Allometric principles were used to discern cross-species differences in (±)-tramadol disposition and formation of its primary analgesic metabolite, (±)-O-desmethyl-tramadol (M1). Species differences in formation of M1 may help predict the analgesic effectiveness of tramadol. Tramadol was administered intravenously by a zero-order (constant infusion) process or rapid bolus dose and racemic concentrations of tramadol and M1 measured. Data were pooled to define differences between species (human, rat, cat, dog, goat, donkey and horse). A two-compartment linear disposition model with first-order elimination was used to describe tramadol and M1 disposition. Slow metabolizers were detected in 6% of the population and tramadol clearance to M1 was 16.2% that of extensive metabolizers. Tramadol clearance to M1 was slower and tramadol clearance by other pathways was faster in rats, dogs, and horses compared to humans. There are substantial differences between species in the pharmacokinetics of tramadol and its M1 metabolite, which are not explained by differences in body weight. The hypothesis that volumes of distribution are similar across species was shown not to be true. M1 exposure in the goat, donkey and cat was comparable to humans, which indicates it is likely to be an effective analgesic at typically used doses in these species but not in dogs or horses.

Comments

This article was originally published in Journal of Pharmacology & Clinical Toxicology, volume 2, issue 1, in 2014.

Recommended Citation

Holford, Sam, Karel Allegaert, Brian Anderson, Butch Kukanich, Altamir B. Sousa, Amir Steinmann, Bruno Pypendop, Reza Mehvar, Mario Giorgi, and Nick Holford. "Parent-Metabolite pharmacokinetic models for tramadol-tests of assumptions and predictions." Journal of Pharmacology & Clinical Toxicology 2.1 (2014).

Copyright

The authors

Creative Commons License

This work is licensed under a Creative Commons Attribution 3.0 License.