title: A Time-Dependent Model Describes Methotrexate Elimination and Supports Dynamic Modification of MRP2/ABCC2 Activity.
abstract: Multidrug resistance protein-2 encoded by the ABCC2 gene (MRP2/ABCC2), an efflux transporter expressed at the proximal renal tubule, is rate-limiting for urine excretion of coproporphyrin (UCP) isomers I and III, translating in high UCP [I/(I + III)] ratio in MRP2-deficient patients presenting with the Dubin-Johnson Syndrome. MRP2 is also a major contributor to methotrexate (MTX) clearance. As MTX is both a substrate and an inhibitor of MRP2, time course of the concentrations of MTX in blood could induce functional modification of MRP2 over time, which in turn can modify its own elimination rate.
  
  
  
  A 3-parameter time-dependent MTX population pharmacokinetic (PK) model based on a power function accounting for nonlinearity in its clearance was developed using Pmetrics in a first cohort of 41 patients (76 PK profiles) and compared with a previously published 2-compartment model developed with NONMEM and a 3-compartment model developed with ITSIM. In a second cohort (62 patients and 62 PK profiles), the association between the UCP [I/(I + III)] ratio at 3 periods [before MTX administration (P1), at the end of infusion (P2), and at hospital discharge (P3)] and the time-dependent PK parameters of MTX was investigated. Effects of genetic polymorphisms and of coadministered drugs were also studied.
  
  
  
  The model developed tightly fitted the data in both cohorts. A significant inverse correlation was found between log (k1) (ie, the rate constant explaining MTX concentration decrease) and the difference in UCP [I/(I + III)] ratio between P3 and P2 (DP3) (β ± SD = -0.025 ± 0.008, P = 0.00443).
  
  
  
  Self-inhibition of the MRP2-dependent secretion of MTX is a plausible explanation for the time-dependent PKs of this drug. Additional studies specifically designed to evaluate this hypothesis are required.
authors.affiliation: *Department of Pharmacology and Toxicology, CHU Limoges; †INSERM UMR 850, University of Limoges, Limoges, France; ‡Laboratory of Biochemistry and Molecular Biology, CHU Tours, Tours, France; §Department of Clinical Hematology, CHU Limoges, Limoges; and ¶Department of Clinical Hematology, La Pitié Salpetrière Hospital, APHP, Paris, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Woillard
authors.forename: Jean
authors.initials: J
authors.lastname: Debord
authors.forename: Isabelle
authors.initials: I
authors.lastname: Benz-de-Bretagne
authors.forename: Franck
authors.initials: F
authors.lastname: Saint-Marcoux
authors.forename: Pascal
authors.initials: P
authors.lastname: Turlure
authors.forename: Stéphane
authors.initials: S
authors.lastname: Girault
authors.forename: Julie
authors.initials: J
authors.lastname: Abraham
authors.forename: Sylvain
authors.initials: S
authors.lastname: Choquet
authors.forename: Pierre
authors.initials: P
authors.lastname: Marquet
authors.forename: Chantal
authors.initials: C
authors.lastname: Barin-Le Guellec
mesh_terms: D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008297:Male; D008727:Methotrexate / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D008875:Middle Aged; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism*; D014556:Urine / Q000737:chemistry
chemical_list: D008727:Methotrexate; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C000715087:ABCC2 protein, human