title: Increased hospital stay and allograft dysfunction in renal transplant recipients with Cyp2c19 AA variant in SNP rs4244285.
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.
authors.affiliation: Unidad de Farmacogenética, Servicio de Farmacia, Hospital Universitario y Politécnico La Fe, Bulevar Sur, S/N. 46026 Valencia, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Bosó
authors.forename: María José
authors.initials: MJ
authors.lastname: Herrero
authors.forename: Sergio
authors.initials: S
authors.lastname: Bea
authors.forename: María
authors.initials: M
authors.lastname: Galiana
authors.forename: Patricia
authors.initials: P
authors.lastname: Marrero
authors.forename: María Remedios
authors.initials: MR
authors.lastname: Marqués
authors.forename: Julio
authors.initials: J
authors.lastname: Hernández
authors.forename: Jaime
authors.initials: J
authors.lastname: Sánchez-Plumed
authors.forename: José Luis
authors.initials: JL
authors.lastname: Poveda
authors.forename: Salvador F
authors.initials: SF
authors.lastname: Aliño
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics* / Q000378:metabolism; D016009:Chi-Square Distribution; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors; D004347:Drug Interactions; D016903:Drug Monitoring; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D016030:Kidney Transplantation / Q000276:immunology*; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics; D009853:Omeprazole / Q000009:adverse effects / Q000493:pharmacokinetics*; D010597:Pharmacogenetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011183:Postoperative Complications / Q000209:etiology / Q000235:genetics*; D054328:Proton Pump Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics*; D013379:Substrate Specificity; D016559:Tacrolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*
chemical_list: D065692:Cytochrome P-450 CYP3A Inhibitors; D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D054328:Proton Pump Inhibitors; D001189:Aryl Hydrocarbon Hydroxylases; C045793:CYP2C19 protein, human; C510164:CYP3A5 protein, human; D065731:Cytochrome P-450 CYP2C19; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D009853:Omeprazole; D016559:Tacrolimus