Association of CYP3A4-392A/G, CYP3A5-6986A/G, and ABCB1-3435C/T Polymorphisms with Tacrolimus Dose, Serum Concentration, and Biochemical Parameters in Mexican Patients with Kidney Transplant

• Published in: Genes 2024-04, Vol.15 (4), p.497
• Main Authors: Alatorre-Moreno, Edith Viridiana, Saldaña-Cruz, Ana Miriam, Pérez-Guerrero, Edsaúl Emilio, Morán-Moguel, María Cristina, Contreras-Haro, Betsabé, López-de La Mora, David Alejandro, Dávalos-Rodríguez, Ingrid Patricia, Marín-Medina, Alejandro, Rivera-Cameras, Alicia, Balderas-Peña, Luz-Ma Adriana, Gómez-Ramos, José Juan, Cortés-Sanabria, Laura, Salazar-Páramo, Mario
• Format: Article
• Language: English
• Subjects: Adult; Analysis; Antihypertensive drugs; ATP Binding Cassette Transporter, Subfamily B - genetics; Creatinine; Cytochrome P-450 CYP3A - genetics; Cytochrome P450; Drug dosages; Enzymes; Female; Gene polymorphism; Genes; Genetic aspects; Genotype; Genotype & phenotype; Graft rejection; Graft Rejection - genetics; Humans; Immunosuppressive agents; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - blood; Immunosuppressive Agents - pharmacokinetics; Kidney transplantation; Kidney Transplantation - adverse effects; Kidneys; Male; Mexico; Middle Aged; Organ transplant recipients; P-Glycoprotein; Patients; Pharmacokinetics; Polymorphism; Polymorphism, Single Nucleotide - genetics; Population; Population studies; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Statistical analysis; Tacrolimus; Tacrolimus - administration & dosage; Tacrolimus - blood; Tacrolimus - pharmacokinetics; Toxicity; Transplantation; Transplants & implants; Variables
• ISSN: 2073-4425; 2073-4425
• DOI: 10.3390/genes15040497

Tacrolimus (TAC) is an immunosuppressant drug that prevents organ rejection after transplantation. This drug is transported from cells via P-glycoprotein (ABCB1) and is a metabolic substrate for cytochrome P450 (CYP) 3A enzymes, particularly CYP3A4 and CYP3A5. Several single-nucleotide polymorphisms (SNPs) have been identified in the genes encoding , , and , including CYP3A4-392A/G (rs2740574), CYP3A5 6986A/G (rs776746), and ABCB1 3435C/T (rs1045642). This study aims to evaluate the association among CYP3A4-392A/G, CYP3A5-6986A/G, and ABCB1-3435C/T polymorphisms and TAC, serum concentration, and biochemical parameters that may affect TAC pharmacokinetics in Mexican kidney transplant (KT) patients. Forty-six kidney transplant recipients (KTR) receiving immunosuppressive treatment with TAC in different combinations were included. CYP3A4, CYP3A5, and gene polymorphisms were genotyped using qPCR TaqMan. Serum TAC concentration (as measured) and intervening variables were assessed. Logistic regression analyses were performed at baseline and after one month to assess the extent of the association between the polymorphisms, intervening variables, and TAC concentration. The GG genotype of CYP3A5-6986 A/G polymorphism is associated with TAC pharmacokinetic variability OR 4.35 (95%CI: 1.13-21.9; = 0.0458) at one month of evolution; in multivariate logistic regression, CYP3A5-6986GG genotype OR 9.32 (95%CI: 1.54-93.08; = 0.028) and the use of medications or drugs that increase serum TAC concentration OR 9.52 (95%CI: 1.79-88.23; = 0.018) were strongly associated with TAC pharmacokinetic variability. The findings of this study of the Mexican population showed that CYP3A5-6986 A/G GG genotype is associated with a four-fold increase in the likelihood of encountering a TAC concentration of more than 15 ng/dL. The co-occurrence of the CYP3A5-6986GG genotype and the use of drugs that increase TAC concentration correlates with a nine-fold increased risk of experiencing a TAC at a level above 15 ng/mL. Therefore, these patients have an increased susceptibility to TAC-associated toxicity.