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European Journal of Drug Metabolism and Pharmacokinetics
Published in: European Journal of Drug Metabolism and Pharmacokinetics 6/2016

01-12-2016 | Original Research Article

A Physiologically Based Pharmacokinetic Model of Amiodarone and its Metabolite Desethylamiodarone in Rats: Pooled Analysis of Published Data

Authors: Jing-Tao Lu, Ying Cai, Feng Chen, Wei-Wei Jia, Zhe-Yi Hu, Yuan-Sheng Zhao

Published in: European Journal of Drug Metabolism and Pharmacokinetics | Issue 6/2016

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Abstract

Background and Objective

Amiodarone (AMD) is one of the most effective drugs for rhythm control of atrial fibrillation. The use of AMD is also associated with adverse effects in multiple tissues. Both the parent compound and its major metabolite desethylamiodarone (DEA) contribute to the drug’s therapeutic and toxic action. The present study aimed to build a whole-body physiologically based pharmacokinetic (PBPK) model for AMD and DEA in rats.

Methods

Pharmacokinetic data from multiple studies were collected. Some of the data were pooled together to develop the PBPK model; others were used to evaluate the model. Development of the model also involved in vitro to in vivo extrapolation based on in vitro metabolism data.

Results

The final model consisted of 11 tissue compartments, including therapeutic target organs and those to which AMD and DEA may be harmful. Model simulations were in good agreement with the observed time courses of the drug–metabolite pair in tissues, under various dosing scenarios. The key pharmacokinetic properties of AMD, such as extensive tissue distribution, substantial storage in the fat tissue, and long half-lives in many tissues, were closely reflected.

Conclusion

The developed PBPK model can be regarded as the first step towards a PBPK–pharmacodynamic model that can used to mechanistically evaluate and explain the high adverse event rate and potentially to determine which factors are the primary drives for experiencing an adverse event.
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Metadata
Title
A Physiologically Based Pharmacokinetic Model of Amiodarone and its Metabolite Desethylamiodarone in Rats: Pooled Analysis of Published Data
Authors
Jing-Tao Lu
Ying Cai
Feng Chen
Wei-Wei Jia
Zhe-Yi Hu
Yuan-Sheng Zhao
Publication date
01-12-2016
Publisher
Springer International Publishing
Published in
European Journal of Drug Metabolism and Pharmacokinetics / Issue 6/2016
Print ISSN: 0378-7966
Electronic ISSN: 2107-0180
DOI
https://doi.org/10.1007/s13318-015-0295-0

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