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Research ArticleArticle

Increased Hospital Stay and Allograft Disfunction in Renal Transplant Recipients with Cyp2c19 AA Variant in SNP rs4244285

Virginia Bosó, María José Herrero, Sergio Bea, María Galiana, Patricia Marrero, María Remedios Marqués, Julio Hernández, Jaime Sánchez-Plumed, José Luis Poveda and Salvador F. Aliño
Drug Metabolism and Disposition February 2013, 41 (2) 480-487; DOI: https://doi.org/10.1124/dmd.112.047977
Virginia Bosó
Unidad de Farmacogenética. Servicio Farmacia, Instituto Investigación Sanitaria La Fe, (V.B., M.J.H., S.F.A.), Servicio Farmacia (V.B., M.G., P.M., M.R.M., J.L.P.), Servicio Nefrología (S.B., J.H., J.S.P.), and Unidad Farmacología Clínica, Hospital Universitario y Politécnico La Fe (S.F.A.), and Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain (S.F.A.)
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María José Herrero
Unidad de Farmacogenética. Servicio Farmacia, Instituto Investigación Sanitaria La Fe, (V.B., M.J.H., S.F.A.), Servicio Farmacia (V.B., M.G., P.M., M.R.M., J.L.P.), Servicio Nefrología (S.B., J.H., J.S.P.), and Unidad Farmacología Clínica, Hospital Universitario y Politécnico La Fe (S.F.A.), and Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain (S.F.A.)
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Sergio Bea
Unidad de Farmacogenética. Servicio Farmacia, Instituto Investigación Sanitaria La Fe, (V.B., M.J.H., S.F.A.), Servicio Farmacia (V.B., M.G., P.M., M.R.M., J.L.P.), Servicio Nefrología (S.B., J.H., J.S.P.), and Unidad Farmacología Clínica, Hospital Universitario y Politécnico La Fe (S.F.A.), and Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain (S.F.A.)
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María Galiana
Unidad de Farmacogenética. Servicio Farmacia, Instituto Investigación Sanitaria La Fe, (V.B., M.J.H., S.F.A.), Servicio Farmacia (V.B., M.G., P.M., M.R.M., J.L.P.), Servicio Nefrología (S.B., J.H., J.S.P.), and Unidad Farmacología Clínica, Hospital Universitario y Politécnico La Fe (S.F.A.), and Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain (S.F.A.)
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Patricia Marrero
Unidad de Farmacogenética. Servicio Farmacia, Instituto Investigación Sanitaria La Fe, (V.B., M.J.H., S.F.A.), Servicio Farmacia (V.B., M.G., P.M., M.R.M., J.L.P.), Servicio Nefrología (S.B., J.H., J.S.P.), and Unidad Farmacología Clínica, Hospital Universitario y Politécnico La Fe (S.F.A.), and Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain (S.F.A.)
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María Remedios Marqués
Unidad de Farmacogenética. Servicio Farmacia, Instituto Investigación Sanitaria La Fe, (V.B., M.J.H., S.F.A.), Servicio Farmacia (V.B., M.G., P.M., M.R.M., J.L.P.), Servicio Nefrología (S.B., J.H., J.S.P.), and Unidad Farmacología Clínica, Hospital Universitario y Politécnico La Fe (S.F.A.), and Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain (S.F.A.)
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Julio Hernández
Unidad de Farmacogenética. Servicio Farmacia, Instituto Investigación Sanitaria La Fe, (V.B., M.J.H., S.F.A.), Servicio Farmacia (V.B., M.G., P.M., M.R.M., J.L.P.), Servicio Nefrología (S.B., J.H., J.S.P.), and Unidad Farmacología Clínica, Hospital Universitario y Politécnico La Fe (S.F.A.), and Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain (S.F.A.)
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Jaime Sánchez-Plumed
Unidad de Farmacogenética. Servicio Farmacia, Instituto Investigación Sanitaria La Fe, (V.B., M.J.H., S.F.A.), Servicio Farmacia (V.B., M.G., P.M., M.R.M., J.L.P.), Servicio Nefrología (S.B., J.H., J.S.P.), and Unidad Farmacología Clínica, Hospital Universitario y Politécnico La Fe (S.F.A.), and Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain (S.F.A.)
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José Luis Poveda
Unidad de Farmacogenética. Servicio Farmacia, Instituto Investigación Sanitaria La Fe, (V.B., M.J.H., S.F.A.), Servicio Farmacia (V.B., M.G., P.M., M.R.M., J.L.P.), Servicio Nefrología (S.B., J.H., J.S.P.), and Unidad Farmacología Clínica, Hospital Universitario y Politécnico La Fe (S.F.A.), and Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain (S.F.A.)
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Salvador F. Aliño
Unidad de Farmacogenética. Servicio Farmacia, Instituto Investigación Sanitaria La Fe, (V.B., M.J.H., S.F.A.), Servicio Farmacia (V.B., M.G., P.M., M.R.M., J.L.P.), Servicio Nefrología (S.B., J.H., J.S.P.), and Unidad Farmacología Clínica, Hospital Universitario y Politécnico La Fe (S.F.A.), and Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, Valencia, Spain (S.F.A.)
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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 (Cmin/[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.

Footnotes

  • This work was partially supported by Consellería de Sanidad, Generalitat Valenciana, [Grants GE-039/11 and GE-007/10].

  • This work has been partially presented at the following two congresses: Bosó V, Herrero MJ, Bea S, Galiana M, Marrero P, Marqués MR, Plumed JS, Hernández J, Poveda JL, Aliño SF (2012) Renal transplantation recipients with AA genotype in SNP rs4244285 of CYP2C19 show an increase in hospital stay duration and allograft dysfunction probably due to increased tacrolimus levels caused by interaction with omeprazole. XXIV International Congress of the Transplantation Society; 2012 Jul 15-19; Berlin, Germany; and Bosó V, Herrero MJ, Bea S, Galiana M, Marrero P, Marqués MR, Plumed JS, Hernández J, Poveda JL, Aliño SF (2012) Niveles de tacrólimus elevados a causa de interacción con omeprazol, provocan en los pacientes con genotipo AA en el SNP rs4244285 de CYP2C19, un incremento en la estancia hospitalaria y posible disfunción del injerto. II Congreso Sociedad Española Trasplante; 2012 June 23-26; Madrid, Spain.

  • dx.doi.org/10.1124/dmd.112.047977.

  • Received July 16, 2012.
  • Accepted November 21, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Drug Metabolism and Disposition: 41 (2)
Drug Metabolism and Disposition
Vol. 41, Issue 2
1 Feb 2013
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Research ArticleArticle

Impact of CYP2C19 Variant on Renal Transplantation

Virginia Bosó, María José Herrero, Sergio Bea, María Galiana, Patricia Marrero, María Remedios Marqués, Julio Hernández, Jaime Sánchez-Plumed, José Luis Poveda and Salvador F. Aliño
Drug Metabolism and Disposition February 1, 2013, 41 (2) 480-487; DOI: https://doi.org/10.1124/dmd.112.047977

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Research ArticleArticle

Impact of CYP2C19 Variant on Renal Transplantation

Virginia Bosó, María José Herrero, Sergio Bea, María Galiana, Patricia Marrero, María Remedios Marqués, Julio Hernández, Jaime Sánchez-Plumed, José Luis Poveda and Salvador F. Aliño
Drug Metabolism and Disposition February 1, 2013, 41 (2) 480-487; DOI: https://doi.org/10.1124/dmd.112.047977
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