Benz-de Bretagne Isabelle, Zahr Noël, Le Gouge Amélie, Hulot Jean-Sébastien, Houillier Caroline, Hoang-Xuan Khe, Gyan Emmanuel, Lissandre Séverine, Choquet Sylvain, Le Guellec Chantal
Laboratoire de Biochimie et Biologie Moléculaire, CHRU de Tours, Tours, France; Université François Rabelais de Tours, PRES Centre Val de Loire Université, EA4245, Tours, France.
Br J Clin Pharmacol. 2014 Aug;78(2):329-42. doi: 10.1111/bcp.12326.
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.
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.
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.
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.
尿中粪卟啉原I/（I + III）比值可能是多药耐药相关蛋白2（MRP2）活性的替代指标。我们对接受甲氨蝶呤（MTX）治疗的患者进行了一项前瞻性研究，以探讨该比值与MRP2底物药代动力学之间的关系。
收集了81例患者的三份尿液样本用于测定尿中粪卟啉原I/（I + III）比值：一份在MTX输注前（P1），一份在MTX输注结束时（P2），一份在出院当天（P3）。分析了ABCC2的三种多态性，并评估了它们与基础尿中粪卟啉原I/（I + III）比值的关系。记录了所有相关药物并赋予药物相互作用评分（DIS）。进行群体药代动力学分析，以评估MTX清除率（MTXCL）是否与基础尿中粪卟啉原I/（I + III）比值、MTX输注期间其变化、DIS或其他常见协变量相关。
基础尿中粪卟啉原I/（I + III）比值与ABCC2多态性无关，且根据DIS无差异。随着时间的推移，该比值有显著变化，P1和P2之间升高，P3时降低（P < 0.001）。基础尿中粪卟啉原I/（I + III）比值与MTXCL之间未发现关联。最终模型表明，MTXCL取决于P1和P3之间比值的变化、DIS和肌酐清除率。
基础尿中粪卟啉原I/（I + III）比值不能预测MTXCL。然而，它对MTX的存在敏感，因此它反映了因药物而改变的功能这一推测是合理的。
