Article ; Online: The Role of Coproporphyrins As Endogenous Biomarkers for Organic Anion Transporting Polypeptide 1B Inhibition-Progress from 2016 to 2023.
Drug metabolism and disposition: the biological fate of chemicals
2023 Volume 51, Issue 8, Page(s) 950–961
Abstract: Since the initial clinical study investigating coproporphyrins I and III (CP-I and CP-III) as endogenous biomarkers for organic anion transporting polypeptide (OATP) inhibition drug-drug interactions (DDIs) published in 2016, significant progress has ... ...
| Abstract | Since the initial clinical study investigating coproporphyrins I and III (CP-I and CP-III) as endogenous biomarkers for organic anion transporting polypeptide (OATP) inhibition drug-drug interactions (DDIs) published in 2016, significant progress has been made in confirming the usefulness of the CPs, particularly CP-I, as biomarkers in assessing OATP functions. CP-I exhibits selectivity toward OATP1B activity in human subjects with genetic variants of OATP1B1. Its sensitivity to a broad spectrum of clinical OATP1B inhibitors has been established from weak to vigorous. Dose-dependent CP-I changes in healthy human subjects show agreement with DDI magnitudes of probe substrates by rifampin treatment. Physiologically based pharmacokinetic models have been established for concentration changes of plasma CP-I with OATP inhibitors, demonstrating the usefulness of supporting the quantitative translation of the effect of CP-I levels into the DDI risk assessment of potential OATP inhibitors. As plasma CP-I's sensitivity, specificity, and selectivity have been validated in humans, monitoring CP-I levels in single and multiple clinical phase I dose escalation studies is recommended for early assessment of DDI risks and understanding the full dose-response of an investigational drug to OATP inhibitions. A decision tree is proposed to preclude the need to conduct a dedicated DDI study by administering a probe substrate drug to human subjects. SIGNIFICANCE STATEMENT: The minireview summarized the validation paths of coproporphyrins I and III (CP-I and CP-III) as biomarkers of organic anion transporting polypeptide 1B (OATP1B) inhibition in humans for their selectivity, specificity, and sensitivity. The utility of monitoring CP-I to assess drug-drug interactions of OATP1B inhibition in early drug development is proposed. Changes in plasma CP-I in phase I dose range studies can be used to frame plans for late-stage development and facilitate the mechanistic understanding of complex drug-drug interactions. |
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| MeSH term(s) | Humans ; Biomarkers ; Coproporphyrins/metabolism ; Drug Interactions ; Organic Anion Transporters/genetics ; Rifampin/therapeutic use |
| Chemical Substances | Biomarkers ; Coproporphyrins ; Organic Anion Transporters ; Rifampin (VJT6J7R4TR) |
| Language | English |
| Publishing date | 2023-07-05 |
| Publishing country | United States |
| Document type | Journal Article ; Review |
| ZDB-ID | 186795-7 |
| ISSN | 1521-009X ; 0090-9556 |
| ISSN (online) | 1521-009X |
| ISSN | 0090-9556 |
| DOI | 10.1124/dmd.122.001012 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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