CYP3A-status is associated with blood concentration and dose-requirement of tacrolimus in heart transplant recipients

Abstract High inter-individual variability in tacrolimus clearance is attributed to genetic polymorphisms of CYP3A enzymes. However, due to CYP3A phenoconversion induced by non-genetic factors, continuous changes in tacrolimus-metabolizing capacity entail frequent dose-refinement for optimal immunos...

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Autores principales:	Máté Déri, Zsófia Szakál-Tóth, Ferenc Fekete, Katalin Mangó, Evelyn Incze, Annamária Minus, Béla Merkely, Balázs Sax, Katalin Monostory
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/432193eb97624b7c9b53b30747e53717
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spelling	oai:doaj.org-article:432193eb97624b7c9b53b30747e537172021-11-08T10:46:02ZCYP3A-status is associated with blood concentration and dose-requirement of tacrolimus in heart transplant recipients10.1038/s41598-021-00942-y2045-2322https://doaj.org/article/432193eb97624b7c9b53b30747e537172021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-00942-yhttps://doaj.org/toc/2045-2322Abstract High inter-individual variability in tacrolimus clearance is attributed to genetic polymorphisms of CYP3A enzymes. However, due to CYP3A phenoconversion induced by non-genetic factors, continuous changes in tacrolimus-metabolizing capacity entail frequent dose-refinement for optimal immunosuppression. In heart transplant recipients, the contribution of patients’ CYP3A-status (CYP3A5 genotype and CYP3A4 expression) to tacrolimus blood concentration and dose-requirement was evaluated in the early and late post-operative period. In low CYP3A4 expressers carrying CYP3A53/3, the dose-corrected tacrolimus level was significantly higher than in normal CYP3A4 expressers or in those with CYP3A51. Modification of the initial tacrolimus dose was required for all patients: dose reduction by 20% for low CYP3A4 expressers, a 40% increase for normal expressers and a 2.4-fold increase for CYP3A51 carriers. The perioperative high-dose corticosteroid therapy was assumed to ameliorate the low initial tacrolimus-metabolizing capacity during the first month. The fluctuation of CYP3A4 expression and tacrolimus blood concentration (C0/D) was found to be associated with tapering and cessation of corticosteroid in CYP3A5 non-expressers, but not in those carrying CYP3A5*1. Although monitoring of tacrolimus blood concentration cannot be omitted, assaying recipients’ CYP3A-status can guide optimization of the initial tacrolimus dose, and can facilitate personalized tacrolimus therapy during steroid withdrawal in the late post-operative period.Máté DériZsófia Szakál-TóthFerenc FeketeKatalin MangóEvelyn InczeAnnamária MinusBéla MerkelyBalázs SaxKatalin MonostoryNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Máté Déri Zsófia Szakál-Tóth Ferenc Fekete Katalin Mangó Evelyn Incze Annamária Minus Béla Merkely Balázs Sax Katalin Monostory CYP3A-status is associated with blood concentration and dose-requirement of tacrolimus in heart transplant recipients
description	Abstract High inter-individual variability in tacrolimus clearance is attributed to genetic polymorphisms of CYP3A enzymes. However, due to CYP3A phenoconversion induced by non-genetic factors, continuous changes in tacrolimus-metabolizing capacity entail frequent dose-refinement for optimal immunosuppression. In heart transplant recipients, the contribution of patients’ CYP3A-status (CYP3A5 genotype and CYP3A4 expression) to tacrolimus blood concentration and dose-requirement was evaluated in the early and late post-operative period. In low CYP3A4 expressers carrying CYP3A53/3, the dose-corrected tacrolimus level was significantly higher than in normal CYP3A4 expressers or in those with CYP3A51. Modification of the initial tacrolimus dose was required for all patients: dose reduction by 20% for low CYP3A4 expressers, a 40% increase for normal expressers and a 2.4-fold increase for CYP3A51 carriers. The perioperative high-dose corticosteroid therapy was assumed to ameliorate the low initial tacrolimus-metabolizing capacity during the first month. The fluctuation of CYP3A4 expression and tacrolimus blood concentration (C0/D) was found to be associated with tapering and cessation of corticosteroid in CYP3A5 non-expressers, but not in those carrying CYP3A5*1. Although monitoring of tacrolimus blood concentration cannot be omitted, assaying recipients’ CYP3A-status can guide optimization of the initial tacrolimus dose, and can facilitate personalized tacrolimus therapy during steroid withdrawal in the late post-operative period.
format	article
author	Máté Déri Zsófia Szakál-Tóth Ferenc Fekete Katalin Mangó Evelyn Incze Annamária Minus Béla Merkely Balázs Sax Katalin Monostory
author_facet	Máté Déri Zsófia Szakál-Tóth Ferenc Fekete Katalin Mangó Evelyn Incze Annamária Minus Béla Merkely Balázs Sax Katalin Monostory
author_sort	Máté Déri
title	CYP3A-status is associated with blood concentration and dose-requirement of tacrolimus in heart transplant recipients
title_short	CYP3A-status is associated with blood concentration and dose-requirement of tacrolimus in heart transplant recipients
title_full	CYP3A-status is associated with blood concentration and dose-requirement of tacrolimus in heart transplant recipients
title_fullStr	CYP3A-status is associated with blood concentration and dose-requirement of tacrolimus in heart transplant recipients
title_full_unstemmed	CYP3A-status is associated with blood concentration and dose-requirement of tacrolimus in heart transplant recipients
title_sort	cyp3a-status is associated with blood concentration and dose-requirement of tacrolimus in heart transplant recipients
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/432193eb97624b7c9b53b30747e53717
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CYP3A-status is associated with blood concentration and dose-requirement of tacrolimus in heart transplant recipients

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