Various effects of repeated rifampin dosing on coproporphyrin levels in humans.

Jonny Kinzi, Markus Grube, Karin Brecht, Isabell Seibert, Werner Siegmund, Henriette E Meyer Zu Schwabedissen

Clinical and translational science 2023 Nov

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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. © 2023 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.

Citation

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. 2023 Nov;16(11):2289-2298