Abstract

MRP2 encoded by ABCC2 gene is involved in the secretion of numerous drugs and endogenous substrates. Patients with Dubin-Johnson syndrome due to mutation in ABCC2 gene have elevated urinary coproporphyrin ratio (UCP I/(I + III)). Here we investigated whether this ratio could serve as a biomarker of MRP2 function. Phenotype-genotype relationships were studied in 74 healthy subjects by measuring individual UCP I/(I + III) ratio obtained on 24-hour urine and by analyzing five common SNPs in ABCC2 gene. The UCP I/(I + III) ratio varied from 14.7% to 46.0% in our population. Subjects with 3972TT genotype had a higher ratio (P = .04) than those carrying the C allele. This higher UCP I/(I + III) ratio was correlated with a higher level of isomer I excretion. This study provides a proof of concept that UCP I/(I + III) ratio can be used as a biomarker of MRP2 function in clinical studies as it provides quantitative information about the in vivo activity of MRP2 in a given patient.

Highlights

  • Excessive accumulation of drugs and consequent druginduced toxicity may arise from a defect in the ability to secrete drugs into the bile or urine

  • This study provides a proof of concept that UCP I/(I + III) ratio can be used as a biomarker of multidrug resistance protein 2 (MRP2) function in clinical studies as it provides quantitative information about the in vivo activity of MRP2 in a given patient

  • Five subjects were excluded from the analysis because we were unable to obtain the totality of samples and one was excluded because he took a nonsteroidal antiinflammatory drug (NSAID) during the study

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Summary

Introduction

Excessive accumulation of drugs and consequent druginduced toxicity may arise from a defect in the ability to secrete drugs into the bile or urine. Various membrane transporters, including those of the ATP-binding cassette (ABC) family, are involved in these processes in the kidneys and liver. One such transporter, multidrug resistance protein 2 (MRP2), encoded by the ABCC2 (ABC subfamily C2) gene, plays a key role in the secretion of numerous drugs and drug metabolites [1]. Studies in Mrp2-deficient rodents have confirmed the relevance of this transporter in drug pharmacokinetics, with exposure levels reaching 140% to 615% of those in normal animals, depending on the drug considered [2,3,4,5]. No direct lines of in vitro evidence indicated a role for MRP2 in coproporphyrins transport, animal studies recently confirmed the major role of Mrp in the elimination of these

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