Various effects of repeated rifampin dosing on coproporphyrin levels in humans
Abstract In recent years, the identification of endogenous substrates as biomarkers became an uprising topic. Particularly coproporphyrins (CPs), byproducts of heme biosynthesis, are intensely investigated as biomarkers for predicting interactions with the organic anion transporting polypeptide (OAT...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-11-01
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| Series: | Clinical and Translational Science |
| Online Access: | https://doi.org/10.1111/cts.13629 |
| _version_ | 1797627426160771072 |
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| author | Jonny Kinzi Markus Grube Karin Brecht Isabell Seibert Werner Siegmund Henriette E. Meyer zu Schwabedissen |
| author_facet | Jonny Kinzi Markus Grube Karin Brecht Isabell Seibert Werner Siegmund Henriette E. Meyer zu Schwabedissen |
| author_sort | Jonny Kinzi |
| collection | DOAJ |
| description | Abstract In recent years, the identification of endogenous substrates as biomarkers became an uprising topic. Particularly coproporphyrins (CPs), byproducts of heme biosynthesis, are intensely investigated as biomarkers for predicting interactions with the organic anion transporting polypeptide (OATP) 1B transporters. In the context of drug–drug interactions, several preclinical and clinical studies assessed the effect of the OATP1B‐index inhibitor rifampin on CPI levels. However, rifampin is not only a “perpetrator” drug of transporters but is also known for its interaction with the nuclear receptor pregnane X receptor (PXR) leading to the efficient induction of PXR‐target genes. These include hemoproteins like cytochrome P450 enzymes but also the δ‐aminolevulinate synthase 1, which is the rate‐limiting enzyme in heme biosynthesis. In this study, we showed that quantification of CPs in clinical serum samples was possible after long‐term storage at −20°C. We quantified CPI, CPIII, and heme levels in clinical serum samples (at selected timepoints) that originated from a trial investigating the interaction potential of repeated rifampin administration in 12 healthy participants. In samples collected at the assumed time to maximum concentration of rifampin, higher CP levels were observed compared to baseline. Increased levels persisted even 14 h after discontinuation of rifampin. No impact on heme serum levels was observed. We found a correlation between CP isomers at baseline and at 14 h after rifampin intake. In summary, we show that multiple doses of rifampin affect CP levels. However, besides inhibition of hepatic OATP function there is evidence for an interaction with CP levels beyond the transporter level. |
| first_indexed | 2024-03-11T10:23:59Z |
| format | Article |
| id | doaj.art-b52058d9d46b43259b547abad28fe453 |
| institution | Directory Open Access Journal |
| issn | 1752-8054 1752-8062 |
| language | English |
| last_indexed | 2024-03-11T10:23:59Z |
| publishDate | 2023-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Clinical and Translational Science |
| spelling | doaj.art-b52058d9d46b43259b547abad28fe4532023-11-16T04:14:35ZengWileyClinical and Translational Science1752-80541752-80622023-11-0116112289229810.1111/cts.13629Various effects of repeated rifampin dosing on coproporphyrin levels in humansJonny Kinzi0Markus Grube1Karin Brecht2Isabell Seibert3Werner Siegmund4Henriette E. Meyer zu Schwabedissen5Biopharmacy, Department of Pharmaceutical Sciences University of Basel Basel SwitzerlandCenter of Drug Absorption and Transport, Institute for Pharmacology University Medicine Greifswald Greifswald GermanyBiopharmacy, Department of Pharmaceutical Sciences University of Basel Basel SwitzerlandBiopharmacy, Department of Pharmaceutical Sciences University of Basel Basel SwitzerlandCenter of Drug Absorption and Transport, Institute for Pharmacology University Medicine Greifswald Greifswald GermanyBiopharmacy, Department of Pharmaceutical Sciences University of Basel Basel SwitzerlandAbstract In recent years, the identification of endogenous substrates as biomarkers became an uprising topic. Particularly coproporphyrins (CPs), byproducts of heme biosynthesis, are intensely investigated as biomarkers for predicting interactions with the organic anion transporting polypeptide (OATP) 1B transporters. In the context of drug–drug interactions, several preclinical and clinical studies assessed the effect of the OATP1B‐index inhibitor rifampin on CPI levels. However, rifampin is not only a “perpetrator” drug of transporters but is also known for its interaction with the nuclear receptor pregnane X receptor (PXR) leading to the efficient induction of PXR‐target genes. These include hemoproteins like cytochrome P450 enzymes but also the δ‐aminolevulinate synthase 1, which is the rate‐limiting enzyme in heme biosynthesis. In this study, we showed that quantification of CPs in clinical serum samples was possible after long‐term storage at −20°C. We quantified CPI, CPIII, and heme levels in clinical serum samples (at selected timepoints) that originated from a trial investigating the interaction potential of repeated rifampin administration in 12 healthy participants. In samples collected at the assumed time to maximum concentration of rifampin, higher CP levels were observed compared to baseline. Increased levels persisted even 14 h after discontinuation of rifampin. No impact on heme serum levels was observed. We found a correlation between CP isomers at baseline and at 14 h after rifampin intake. In summary, we show that multiple doses of rifampin affect CP levels. However, besides inhibition of hepatic OATP function there is evidence for an interaction with CP levels beyond the transporter level.https://doi.org/10.1111/cts.13629 |
| spellingShingle | Jonny Kinzi Markus Grube Karin Brecht Isabell Seibert Werner Siegmund Henriette E. Meyer zu Schwabedissen Various effects of repeated rifampin dosing on coproporphyrin levels in humans Clinical and Translational Science |
| title | Various effects of repeated rifampin dosing on coproporphyrin levels in humans |
| title_full | Various effects of repeated rifampin dosing on coproporphyrin levels in humans |
| title_fullStr | Various effects of repeated rifampin dosing on coproporphyrin levels in humans |
| title_full_unstemmed | Various effects of repeated rifampin dosing on coproporphyrin levels in humans |
| title_short | Various effects of repeated rifampin dosing on coproporphyrin levels in humans |
| title_sort | various effects of repeated rifampin dosing on coproporphyrin levels in humans |
| url | https://doi.org/10.1111/cts.13629 |
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