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

Aims The urinary coproporphyrin I /( I + III ) ratio may be a surrogate for MRP 2 activity. We conducted a prospective study in patients receiving methotrexate ( MTX ) to examine the relationship between this ratio and the pharmacokinetics of a MRP 2 substrate. Methods Three urine samples were collected from 81 patients for UCP I /( I + III ) ratio determination: one before ( P 1), one at the end of MTX infusion ( P 2), and one on the day of hospital discharge ( P 3). Three polymorphisms of ABCC 2 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 ABCC 2 polymorphisms and did not differ according to the DIS . Significant changes in the ratio were observed over time, with an increase between P 1 and P 2 and a decrease at P 3 ( 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 P 1 and P 3, 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.