A Highly Selective and Sensitive LC–MS/HRMS Assay for Quantifying Coproporphyrins as Organic Anion-Transporting Peptide Biomarkers

Abstract

Aim: Coproporphyrin-I (CP-I) and coproporphyrin-III (CP-III) in plasma and urine have been proposed as biomarkers for assessing drug–drug interactions involving hepatic drug transporters such as organic anion-transporting peptides (OATP), 1B1 and 1B3. Materials & methods: Plasma and urine extracts were analyzed for CP-I/CP-III using a TripleTOF API6600 mass spectrometer. Results: Previously unreported, CP-I/CP-III doubly charged ions (m/z 328.14) were used as precursor ions to improve the assay sensitivity and selectivity over the singly charged precursor ions (m/z 655.28). Levels of CP-I and CP-III measured ranged 0.45–1.1 and 0.050–0.50 ng/ml in plasma and 5–35 and 1–35 ng/ml in urine, respectively. Conclusion: The described highly selective and sensitive CP-I/CP-III LC–HRMS assay offers options for earlier characterization and clinical safety projections for OATP1B1/3-mediated drug–drug interactions along with pharmacokinetic analyses of a new chemical entity as part of first-in-human clinical studies.

Keywords::

• biomarkers
• coproporphyrin
• drug–drug interactions
• high-resolution mass spectrometry
• organic anion-transporting peptides

Supplementary Data

Financial & competing interests disclosure

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Acknowledgements

The authors gratefully acknowledge Pfizer PDM department colleagues SL Becker, CK Taylor and D Mercure for helping with sample logistical details. Authors also thank Y Weng, LM Tremaine, TC Wilson and DO Scott for helpful discussions and providing continued support.