Influence of donor liver CYP3A4*20 loss-of-function genotype on tacrolimus pharmacokinetics in transplanted patients Miguel A. Gómez-Bravo a,b, *, María Apellaniz-Ruiz d, *, Magdalena Salcedo e , Constantino Fondevila f , Francisco Suarez j , José Castellote g , Sebastián Rufian k , José A. Pons l , Itxarone Bilbao b,h , José M. Alamo a,b , Olga Millán b,i , Mercè Brunet b,i,† and Cristina Rodríguez-Antona c,d,† 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 (C 0 ), and dose-adjusted tacrolimus trough concentrations (C 0 /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 C 0 /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 C 0 /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 C 0 /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. Pharmacogenetics and Genomics 00:000–000 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Pharmacogenetics and Genomics 2017, 00:000–000 Keywords: CYP3A4*20 allele, genotyping, liver transplant, tacrolimus a Liver Transplant Unit, Virgen del Rocío University Hospital, Sevilla, b Liver and Digestive Diseases Networking Biomedical Research Centre (CIBERehd), c Rare Diseases Networking Biomedical Research Centre (CIBERER), d Hereditary Endocrine Cancer Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), e Liver Transplant Unit, Gregorio Marañón Hospital, Madrid, f General Surgery and Digestive Unit, Clinical and Provincial Hospital of Barcelona, g Digestive Unit, Bellvitge University Hospital, h Liver Transplant Unit, Vall d’Hebron University Hospital, i Pharmacology and Toxicology Laboratory, Centre de Diagnòstic Biomèdic, IDIBAPS, Hospital Clinic, University of Barcelona, Barcelona, j Liver Transplant Unit, Hospitals of A Coruña, A Coruña, k General Surgery and Digestive Unit, Reina Sofia University Hospital, Córdoba and l Liver Transplant Unit, Hospital Clínico Universitario Virgen de la Arrixaca, IMIB, Murcia, Spain Correspondence to Cristina Rodríguez-Antona, Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain Tel: + 34 917 328 000; fax: + 34 912 246 972; e-mail: crodriguez@cnio.es *Miguel A. Gómez-Bravo and María Apellaniz-Ruiz contributed equally to the writing of this article. †Mercè Brunet and Cristina Rodríguez-Antona contributed equally to the writing of this article. Received 5 April 2017 Accepted 24 August 2017 Introduction Cytochrome P450 3A4 (CYP3A4) is a key enzyme for the metabolism of more than half of all clinical drugs, con- tributing critically toward the hepatic metabolism of drugs and also the first-pass metabolism of orally admi- nistered compounds [1,2]. There is high variability in CYP3A4 expression, which contributes toward unpre- dictable drug responses and toxicities. Evidences suggest that considerable heritability underlies this variation [3], but few common variants influencing CYP3A4 activity have been identified [4]. Among these, only CYP3A4*22 (rs35599367), an intronic variant leading to decreased mRNA expression [5], has been validated consistently. Three CYP3A4 frameshift variants leading to premature stop codons (CYP3A4*6, CYP3A4*20, and CYP3A4*26) and more than 20 missense variants are annotated in the Human CYP Allele Nomenclature Database (http://www. cypalleles.ki.se/). Although individually these CYP3A4 loss- of-function and missense variants are rare, altogether, they may affect a high proportion of the population [6]. Moreover, recently we found that the CYP3A4*20 allele is carried by 1.2% of the Spanish population because of a founder effect [7]. Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website, www.pharmacogeneticsandgenomics.com. Original article 1 1744-6872 Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/FPC.0000000000000321 Copyright r 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.