Coproporphyrine Isomers and Methotrexate Elimination
Coproporphyrine Isomers and Methotrexate Elimination
High dose methotrexate (MTX) is responsible of severe toxicity in patients in whom
 elimination from plasma is delayed. Factors responsible for MTX accumulation are partly known
 but some patients still experience toxicity despite adequate measures being taken. Our
 hypothesis is that renal tubular secretion may be impaired in these patients. This study aims
 at evaluating the performance of the UCP ratio (urinary ratio of coproporphyrins), a putative
 biomarker of tubular secretion, in predicting delayed MTX elimination.
MTX is a substrate of MRP2, a renal tubular transporter encoded by the ABCC2 gene. It has
 been shown that single nucleotide polymorphisms (SNPs) on the ABCC2 gene are associated with
 impairment of MTX elimination. Mutations on the ABCC2 gene are also responsible for the
 Dubin-Johnson syndrome, characterised by the absence of a functional MRP2 protein. Apart from
 hyperbilirubinaemia, the main biological perturbation observed in this disease is a typical
 increase of the urinary ratio of coproporphyrins I (I+ III) (UCP ratio). Our hypothesis is
 that the UCP ratio could be used as a biomarker of MRP2's activity, thus predicting MTX
 elimination. One hundred patients treated with high dose MTX will be recruited in this
 prospective study. Their UCP ratio will be measured before and after MTX administration and
 correlated with MTX clearance. A genetic analysis will be conducted to study the five more
 frequents SNPs of ABCC2 in each patient.
Inclusion criteria :

 -  Patients receiving HDMTX (≥1g/m2) for a primitive cerebral lymphoma, a large cell
 lymphoma, a lymphoblastic lymphoma, a Burkitt's lymphoma or an acute lymphoblastic
 leukaemia,

 -  over 18 years old,

 -  Signed informed consent.

 -  Affiliated to a medical assurance.

 -  Able to respect the protocol.

 -  Effective contraception for women.

 Exclusion criteria :

 -  renal failure,

 -  liver failure,

 -  hepatic cytolysis,

 -  chronic respiratory deficiency,

 -  pregnancy,

 -  breast-feeding,

 -  Concomitant medication: phenytoin, probenecid, trimethoprim, phenylbutazone,
 salicylates, non steroid anti-inflammatory, yellow fever vaccine.

 -  Patient included in another study in the four weeks preceding his inclusion.