Increased hospital stay and allograft dysfunction in renal transplant recipients with Cyp2c19 AA variant in SNP rs4244285.

Autores de IIS La Fe

• Virginia Bosó Ribelles

  Autor

• María José Herrero Cervera

  Autor

• Sergio Bea Granell

  Autor

• Maria Galiana Sastre

  Autor

• Patricia Marrero Alvarez

  Autor

• María Remedios Marques Miñana

  Autor

• Julio Hernández Jaras

  Autor

• Jaime Sanchez Plumed

  Autor

• José Luis Poveda Andrés

  Autor

• Salvador F Aliño Pellicer

  Autor

Grupos

• Farmacogenética

Abstract

Pharmacogenetics correlates certain genetic variants, such as single nucleotide polymorphisms (SNPs), with blood drug levels, efficacy, and adverse effects of the treatment. Tacrolimus is mainly metabolized via CYP3A4/5, whereas CYP2C19 and CYP3A4/5 are responsible for omeprazole metabolism. Omeprazole inhibits tacrolimus metabolism via CYP3A5 in patients carrying variant alleles of CYP2C19, increasing tacrolimus blood concentrations. Seventy-five renal transplant recipients treated with tacrolimus and concomitant omeprazole were genotyped in a panel of 37 SNPs with use of Sequenom MassArray. The patients with CYP2C19*2/*2 genotype (n = 4) showed a median posttransplantation hospital stay of 27.5 days (95% confidence interval [CI], 23-39 days), compared with 12 days (95% CI, 10-15 days) in patients with CYP2C19*1/*1 or CYP2C19*1/*2 (n = 71; P = 0.016, Kruskal-Wallis test).The difference in hospital stay was directly correlated with an increase in tacrolimus levels (C(min)/[dose/weight]) during the first week after trasplantation (in 59 patients with data on levels; P = 0.021, Kruskal-Wallis), excluding the patients with atypical metabolisms due to CYP3A5*1/*3 or CYP3A5*1/*1 genotype. Recipients with CYP2C19*2/*2 genotype also showed allograft delayed function (acute tubular necrosis in 3 patients). Genotyping of CYP3A5 and CYP2C19 in renal transplantation should be considered to be of interest when treating with tacrolimus and omeprazole, because CYP2C19*2/*2 variant indirectly elicits an increase of tacrolimus blood levels and, in our study population, the adverse effects described.

Keywords

• SINGLE-NUCLEOTIDE POLYMORPHISMS; TACROLIMUS DOSE REQUIREMENTS; PROTON PUMP INHIBITORS; GENETIC POLYMORPHISMS; ABCB1 POLYMORPHISMS; PHARMACOGENETIC POLYMORPHISMS; HEART-TRANSPLANTATION; BLOOD-CONCENTRATION; CYP3A5; PHARMACOKINETICS