title: Urinary coproporphyrin I/(I + III) ratio as a surrogate for MRP2 or other transporter activities involved in methotrexate clearance.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: 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.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Benz-de Bretagne
authors.forename: Noël
authors.initials: N
authors.lastname: Zahr
authors.forename: Amélie
authors.initials: A
authors.lastname: Le Gouge
authors.forename: Jean-Sébastien
authors.initials: JS
authors.lastname: Hulot
authors.forename: Caroline
authors.initials: C
authors.lastname: Houillier
authors.forename: Khe
authors.initials: K
authors.lastname: Hoang-Xuan
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Gyan
authors.forename: Séverine
authors.initials: S
authors.lastname: Lissandre
authors.forename: Sylvain
authors.initials: S
authors.lastname: Choquet
authors.forename: Chantal
authors.initials: C
authors.lastname: Le Guellec
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D015415:Biomarkers / Q000652:urine; D003306:Coproporphyrins / Q000652:urine*; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000652:urine; D008297:Male; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use / Q000633:toxicity; D008875:Middle Aged; D008954:Models, Biological; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D003306:Coproporphyrins; D008727:Methotrexate; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C000715087:ABCC2 protein, human; C026971:coproporphyrin III; C031467:coproporphyrin I
keywords: MRP2 (multi-drug resistance protein-2)/ABCC2; benzimidazole; drug transporters; drug-drug interactions; methotrexate; population pharmacokinetics