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Influence of donor liver CYP3A4*20 loss-of-function genotype on tacrolimus pharmacokinetics in transplanted patients.
Gómez-Bravo, Miguel A; Apellaniz-Ruiz, María; Salcedo, Magdalena; Fondevila, Constantino; Suarez, Francisco; Castellote, José; Rufian, Sebastián; Pons, José A; Bilbao, Itxarone; Alamo, José M; Millán, Olga; Brunet, Mercè; Rodríguez-Antona, Cristina.
Afiliación
  • Gómez-Bravo MA; Liver Transplant Unit, Virgen del Rocío University Hospital, Sevilla.
  • Apellaniz-Ruiz M; Liver and Digestive Diseases Networking Biomedical Research Centre (CIBERehd).
  • Salcedo M; Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO).
  • Fondevila C; Liver Transplant Unit, Gregorio Marañón Hospital, Madrid.
  • Suarez F; General Surgery and Digestive Unit, Clinical and Provincial Hospital of Barcelona.
  • Castellote J; Liver Transplant Unit, Hospitals of A Coruña, A Coruña.
  • Rufian S; Digestive Unit, Bellvitge University Hospital.
  • Pons JA; General Surgery and Digestive Unit, Reina Sofia University Hospital, Córdoba.
  • Bilbao I; Liver Transplant Unit, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB, Murcia, Spain.
  • Alamo JM; Liver and Digestive Diseases Networking Biomedical Research Centre (CIBERehd).
  • Millán O; Liver Transplant Unit, Vall d'Hebron University Hospital.
  • Brunet M; Liver Transplant Unit, Virgen del Rocío University Hospital, Sevilla.
  • Rodríguez-Antona C; Liver and Digestive Diseases Networking Biomedical Research Centre (CIBERehd).
Pharmacogenet Genomics ; 28(2): 41-48, 2018 02.
Article en En | MEDLINE | ID: mdl-29256966
ABSTRACT

OBJECTIVE:

Cytochrome P450 3A4 (CYP3A4) metabolizes about half of all drugs on the market; however, the impact of CYP3A4 loss-of-function variants on drug exposures remains poorly characterized. Here, we report the effect of the CYP3A4*20 frameshift allele in two Spanish liver transplant patients treated with tacrolimus. PATIENTS AND

METHODS:

A series of 90 transplanted patients (with DNA available for 89 of the recipients and 76 of the liver donors) treated with tacrolimus were included in the study. The genotypes of liver donors and of the recipients for CYP3A4*20 (rs67666821), CYP3A4*22 (rs35599367) and CYP3A5*3 (rs776746) were compared with weight-adjusted tacrolimus dose (D), tacrolimus trough concentration (C0), and dose-adjusted tacrolimus trough concentrations (C0/D) using the Mann-Whitney U-nonparametric test.

RESULTS:

The CYP3A4*20 allele was detected in two of the liver donors. This genotype yielded at all times higher C0/D (2.6-fold, average) than intermediate CYP3A metabolizers (CYP3A4*1/*1 and CYP3A5*3/*3) (P=0.045, 90 days after transplantation). CYP3A4*22 carriers showed a 1.9-fold average increase in C0/D (P=0.047, 0.025, and 0.053; at days 7, 14, and 30 after transplantation, respectively) compared with intermediate metabolizers. In terms of recipients' genotype, CYP3A5*1 had reduced (P=0.025) and CYP3A4*22 increased C0/D (P=0.056) 7 days after transplantation. The incidence of biopsy-proven acute rejection was 0, 12, and 20% for livers with poor, intermediate, and extensive CYP3A-metabolizing capacity, respectively (P=0.0995).

CONCLUSION:

This first description of CYP3A4*20 null genotype in liver-transplanted patients, supports the relevance of CYP3A genotyping in tacrolimus therapy.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Tacrolimus / Citocromo P-450 CYP3A / Rechazo de Injerto / Inmunosupresores Límite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Pharmacogenet Genomics Asunto de la revista: FARMACOLOGIA / GENETICA MEDICA Año: 2018 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Tacrolimus / Citocromo P-450 CYP3A / Rechazo de Injerto / Inmunosupresores Límite: Adult / Aged / Female / Humans / Male / Middle aged Idioma: En Revista: Pharmacogenet Genomics Asunto de la revista: FARMACOLOGIA / GENETICA MEDICA Año: 2018 Tipo del documento: Article