Urinary coproporphyrin I/(I + III) ratio as a surrogate for MRP2 or other transporter activities involved in methotrexate clearance

Abstract

Aims The urinary coproporphyrin I/(I + III) ratio may be a surrogate for MRP2 activity. We conducted a prospective study in patients receiving methotrexate (MTX) to examine the relationship between this ratio and the pharmacokinetics of a MRP2 substrate. Methods Three urine samples were collected from 81 patients for UCP I/(I + III) ratio determination: one before (P1), one at the end of MTX infusion (P2), and one on the day of hospital discharge (P3). Three polymorphisms of ABCC2 were analysed and their relationships with basal UCP I/(I + III) ratio values assessed. All associated drugs were recorded and a drug interaction score (DIS) was assigned. Population pharmacokinetic analysis was conducted to assess whether MTX clearance (MTXCL) was associated with the basal UCP I/(I + III) ratio, its variation during MTX infusion, the DIS or other common covariates. Results The basal UCP I/(I + III) ratio was not associated with ABCC2 polymorphisms and did not differ according to the DIS. Significant changes in the ratio were observed over time, with an increase between P1 and P2 and a decrease at P3 (P < 0.001). No association was found between basal UCP I/(I + III) ratio and MTXCL. The final model indicates that MTXCL was dependent on the change in the ratio between P1 and P3, DIS and creatinine clearance. Conclusion The basal UCP I/(I + III) ratio is not predictive of MTXCL. However, it is sensitive to the presence of MTX, so it is plausible that it reflects a function modified in response to the drug.

Detection of Weak Organic Anion–Transporting Polypeptide 1B Inhibition by Probenecid with Plasma-Based Coproporphyrin in Humans

“…Moreover, PROB is a weak inhibitor of MRP2 that is expressed on the apical surface of renal proximal tubule epithelial cells and hepatocytes. CPI and CPIII are substrates for MRP2 (Gilibili et al, 2017, Kunze et al, 2018, and the urinary CPI/(CPI + CPIII) ratio was proposed as a surrogate for MRP2 activity (Benz-de Bretagne et al, 2011, Benz-de Bretagne et al, 2014.…”

Identification of Endogenous Biomarkers to Predict the Propensity of Drug Candidates to Cause Hepatic or Renal Transporter-Mediated Drug-Drug Interactions

“…By analyzing 5 common SNPs in the ABCC2 gene, subjects with the 3972TT genotype showed a higher urinary CP ratio than those carrying the C allele. 67 These studies suggest that MRP2 may be involved in hepatobiliary excretion of CPs; however, additional in vitro and in vivo data are required to confirm this hypothesis. In summary, CP I and III could be suitable biomarkers for inhibition of OATP1B, but more in vitro and clinical data are needed to establish its sensitivity and specificity.…”

Coproporphyrin-I: A Fluorescent, Endogenous Optimal Probe Substrate for ABCC2 (MRP2) Suitable for Vesicle-Based MRP2 Inhibition Assay

“…Coproporphyrin I (CP-I) is one of coproporphyrin byproducts of heme biosynthesis. In the liver, CP-I is taken up into hepatocytes by organic anion-transporting polypeptide transporters and effluxed into bile likely by MRP2 (Benz-de Bretagne et al, 2011, 2014Lai et al, 2016;Shen et al, 2016). As such, a higher proportion of CP-I is secreted into the urine of subjects with Dubin-Johnson syndrome compared with normal subjects.…”