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.
摘要:
近年来,内源性底物作为生物标志物的鉴定成为一个上升的话题.特别是卟啉(CP),血红素生物合成的副产物,作为预测与有机阴离子转运多肽(OATP)1B转运蛋白相互作用的生物标志物进行了深入研究。在药物-药物相互作用的背景下,多项临床前和临床研究评估了OATP1B指数抑制剂利福平对CPI水平的影响.然而,利福平不仅是转运蛋白的“犯罪者”药物,而且还以其与核受体孕烷X受体(PXR)的相互作用而闻名,从而导致PXR靶基因的有效诱导。这些包括血液蛋白,如细胞色素P450酶,还有δ-氨基乙酰丙酸合酶1,它是血红素生物合成中的限速酶。在这项研究中,我们表明,在-20°C下长期储存后,可以对临床血清样品中的CPs进行定量。我们量化了CPI,CPIII,和临床血清样本中的血红素水平(在选定的时间点),该样本来自一项试验,该试验调查了12名健康参与者重复利福平的相互作用潜力。在假定的利福平tmax下收集的样本中,与基线相比,观察到更高的CP水平.甚至在停止利福平后14小时,水平的增加持续。未观察到对血红素血清水平的影响。我们发现基线时和摄入利福平后14小时的卟啉异构体之间存在相关性。总之,我们显示多剂量利福平影响CP水平.然而,除了抑制肝脏OATP功能外,还有证据表明与转运蛋白水平以外的CP水平相互作用。