Pharmacogenetics of immunosuppressant drugs: A new aspect for individualized therapy

Abstract

In recent years, pharmacogenetics has emerged as an important tool for choosing the right immunosuppressant drug and its appropriate dose. Indeed, pharmacogenetics may exert its action on immunosuppressant drugs at three levels. Pharmacogenetics identifies and studies the genes involved in encoding the proteins involved in drug pharmacokinetics and in encoding the enzymes involved in drug degradation. Pharmacogenetics is also relevant in encoding the enzymes and proteins involved in codifying the transmembrane proteins involved in transmembrane passage favoring the absorption and intracellular action of several immunosuppressants. Pharmacogenetics concern the variability of genes encoding the proteins involved as immunosuppressant triggers in the pharmacodynamic pathways. Of course, not all genes have been discovered and studied, but some of them have been clearly examined and their relevance together with other factors such as age and race has been defined. Other genes on the basis of relevant studies have been proposed as good candidates for future studies. Unfortunately, to date, clear conclusions may be drawn only for those drugs that are metabolized by CYP3A5 and its genotyping before kidney, heart and lung transplantation is recommended. The conclusions of the studies on the recommended candidate genes, together with the development of omics techniques could in the future allow us to choose the right dose of the right immunosuppressant for the right patient.

The Value of Pharmacogenomics for White and Indigenous Americans after Kidney Transplantation

“…Pharmacogenomic (PGx) studies of genetic polymorphisms in drug-metabolizing enzymes, transporters, receptors, and drug targets may help to explain inter-individual variations in the drug efficacy and toxicity [ 1 , 2 , 3 , 4 ]. This information can provide significant insights to guide drug dosing and identify patients at risk of adverse drug reactions or a lack of drug efficacy.…”

Unraveling the Genomic Architecture of the CYP3A Locus and ADME Genes for Personalized Tacrolimus Dosing

“…CYP3A4*22 and CYP3A4*20 expression, as well as genetic variations in ABCB1, POR, PPARA, and NR1I2 genes all appear to impact tacrolimus pharmacokinetics, but seem to be less clinically relevant than variants in CYP3A4 and CYP3A5. 3 With available data regarding the impact of CYP3A5 genotype variants on tacrolimus, the Clinical Pharmacogenetics Implementation Consortium group has published specific dosing recommendations based on individual patient genotyping. 4 In this edition of Transplantation, Yoon et al 5 present an important analysis outlining the impact of pharmacogenetic variants on tacrolimus in >1100 Korean patients.…”

“…These include patient age, gender, kidney or liver function, hematocrit, plasma albumin concentrations, body surface area, and concomitant medications. 3 Population pharmacokinetic models, an approach combining the above-listed factors with known genetic information, have been used to create dosing algorithms to more precisely forecast a patient’s tacrolimus dose requirements. However, these models require external validation and prospective trialing.…”

A farmacogenômica como preditor de resposta ao tacrolimo em pacientes transplantados de fígado

“…A farmacocinética e a farmacodinâmica são influenciadas pela variabilidade genética de um indivíduo (11). As concentrações plasmáticas do tacrolimo são afetadas pela variabilidade genética tanto do receptor (ação intestina) quanto do doador (ação hepática) (12), por consequência da metabolização extensa das enzimas CYP3A5 e CYP3A4 e do citocromo P450 oxidoreductase (POR) (em menores quantidades) presentes no intestino delgado e no fígado (13).…”

“…O estudo da farmacogenética ocorre por meio da identificação de genes relacionados à codificação de proteínas envolvidas na farmacocinética, na farmacodinâmica e/ou nas proteínas transmembranas (11). O termo polimorfismo genético é frequentemente utilizado em situações em que ocorrem variações na sequência de ácido desoxirribonucleico (DNA).…”