Delivery of amitriptyline by intravenous and intraperitoneal administration compared in the same animal by whole-body mass spectrometry imaging of a stable isotope labelled drug substance in mice

ABSTRACT

Background: The distribution and metabolism of a drug in the organism are dependent on the administration route as well as on the drug formulation. It is important to be able to assess which impact the administration route or formulation of a drug has for its distribution and metabolism.

Methods: The antidepressant drug amitriptyline was intravenously (IV) dosed to a mouse and immediately after, a similar amount of a deuterium-labeled version of the drug was intraperitoneally (IP) dosed to the same animal. Whole-body cryo-sections were made at t = 5, 15, 30, and 60 min post-dosing, and the two drug substances and metabolites were imaged by DESI-MS/MS.

Results: After 5 min, the IV dosed drug was detected throughout the animal, while the IP dosed drug was primarily found in the abdominal cavity. At later times, the differences between the two administration routes became less pronounced. Two administration routes provided highly similar metabolite distributions, also at early time points.

Conclusion: The method provides a unique way to compare delivery and metabolism of a drug by different administration routes or formulations in the very same animal, eliminating uncertainties caused by animal-to-animal variation and avoiding the use of radioactive labeling.

KEYWORDS:

• Drug distribution
• drug administration
• mass spectrometry imaging
• whole-body imaging
• drug metabolism
• DESI-MS

Acknowledgments

The authors are thankful to Bjarne Styrishave for useful discussions on drug metabolism.

Author contributions

L Morineau performed the cryo-sectioning and the imaging work under the supervision and guidance of S Jacobsen. K Kleberg conducted the animal experiments. H Hansen and C Janfelt conceived the study. C Janfelt wrote the manuscript with contributions from all other authors.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Supplementary material

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Additional information

Funding

The authors were supported by the Carlsberg Foundation and by The Danish Council for Independent Research | Medical Sciences [grant no. DFF – 4002-00391]. K Kleberg was supported by a grant from the Lundbeck Foundation