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Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients.

08:00 EDT 19th June 2018 | BioPortfolio

Summary of "Genotypes associated with tacrolimus pharmacokinetics impact clinical outcomes in lung transplant recipients."

Most lung transplantation immunosuppression regimens include tacrolimus. Single nucleotide polymorphisms (SNPs) in genes important to tacrolimus bioavailability and clearance (ABCB1, CYP3A4 and CYP3A5) are associated with differences in tacrolimus pharmacokinetics. We hypothesized that polymorphisms in these genes would impact immunosuppression-related outcomes. We categorized ABCB1, CYP3A4, and CYP3A5 SNPs for 321 lung allograft recipients. Genotype effects on time to therapeutic tacrolimus level, interactions with antifungal medications, concentration to dose (C /D), acute kidney injury, and rejection were assessed using linear models adjusted for subject characteristics and repeat measures. Compared with CYP3A poor metabolizers (PM), time to therapeutic tacrolimus trough was increased by 5.1±1.6 days for CYP3A extensive metabolizers (EM, p<0.001). In the post-operative period, CYP3A intermediate metabolizers spent 1.2±0.5 days less (p=0.01) and EM spent 2.1±0.5 days less (p<0.001) in goal tacrolimus range than CYP3A PM. Azole antifungals interacted with CYP3A genotype in predicting C /D (p<0.001). Increased acute kidney injury rates were observed in subjects with high ABCB1 function (OR 3.0, 95% CI 1.1-8.6, p=0.01). Lower rates of acute cellular rejection were observed in subjects with low ABCB1 function (OR 0.36, 95% CI 0.07-0.94, p=0.02). Recipient genotyping may help inform tacrolimus dosing decisions and risk of adverse clinical outcomes. This article is protected by copyright. All rights reserved.

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Journal Details

This article was published in the following journal.

Name: Clinical transplantation
ISSN: 1399-0012
Pages: e13332

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Medical and Biotech [MESH] Definitions

A 12-KDa tacrolimus binding protein that is found associated with and may modulate the function of calcium release channels. It is a peptidyl-prolyl cis/trans isomerase which is inhibited by both tacrolimus (commonly called FK506) and SIROLIMUS.

A family of immunophilin proteins that bind to the immunosuppressive drugs TACROLIMUS (also known as FK506) and SIROLIMUS. EC 5.2.1.-

A serine threonine kinase that controls a wide range of growth-related cellular processes. The protein is referred to as the target of RAPAMYCIN due to the discovery that TACROLIMUS (commonly known as rapamycin) forms an inhibitory complex with TACROLIMUS BINDING PROTEIN 1A that blocks the action of its enzymatic activity.

The attempt to improve the PHENOTYPES of future generations of the human population by fostering the reproduction of those with favorable phenotypes and GENOTYPES and hampering or preventing BREEDING by those with "undesirable" phenotypes and genotypes. The concept is largely discredited. (McGraw-Hill Dictionary of Scientific and Technical Terms, 6th ed)

The regular and simultaneous occurrence in a single interbreeding population of two or more discontinuous genotypes. The concept includes differences in genotypes ranging in size from a single nucleotide site (POLYMORPHISM, SINGLE NUCLEOTIDE) to large nucleotide sequences visible at a chromosomal level.

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