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.
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.
Authors: Laura B Ramsey; Gitte H Bruun; Wenjian Yang; Lisa R Treviño; Selina Vattathil; Paul Scheet; Cheng Cheng; Gary L Rosner; Kathleen M Giacomini; Yiping Fan; Alex Sparreboom; Torben S Mikkelsen; Thomas J Corydon; Ching-Hon Pui; William E Evans; Mary V Relling Journal: Genome Res Date: 2011-12-06 Impact factor: 9.043
Authors: Mikko Niemi; Katja A Arnold; Janne T Backman; Marja K Pasanen; Ute Gödtel-Armbrust; Leszek Wojnowski; Ulrich M Zanger; Pertti J Neuvonen; Michel Eichelbaum; Kari T Kivistö; Thomas Lang Journal: Pharmacogenet Genomics Date: 2006-11 Impact factor: 2.089
Authors: Laura B Ramsey; John C Panetta; Colton Smith; Wenjian Yang; Yiping Fan; Naomi J Winick; Paul L Martin; Cheng Cheng; Meenakshi Devidas; Ching-Hon Pui; William E Evans; Stephen P Hunger; Mignon Loh; Mary V Relling Journal: Blood Date: 2012-12-11 Impact factor: 22.113
Authors: S Toh; M Wada; T Uchiumi; A Inokuchi; Y Makino; Y Horie; Y Adachi; S Sakisaka; M Kuwano Journal: Am J Hum Genet Date: 1999-03 Impact factor: 11.025
Authors: Jelmer J van Zanden; Anika de Mul; Heleen M Wortelboer; Mustafa Usta; Peter J van Bladeren; Ivonne M C M Rietjens; Nicole H P Cnubben Journal: Biochem Pharmacol Date: 2005-04-13 Impact factor: 5.858