CYP3A5 and UGT1A9 Polymorphisms Influence Immunosuppressive Therapy in Pediatric Kidney Transplant Recipients

作者：Paola Krall, Dominique Yáñez, Angélica Rojo, Ángela Delucchi, Miguel Córdova‐Delgado, Jorge Morales, Pía Boza, Alonso de la Rivera, Natalie Espinoza, Natalia Armijo, Luis E. Castañeda, Mauricio J. Farfán, Carolina Salas · 发表于：Frontiers in Pharmacology · 年份：2021 · DOI：10.3389/fphar.2021.653525 · 被引用次数：16 · 研究领域：Renal Transplantation Outcomes and Treatments、Pharmacological Effects and Toxicity Studies、HIV/AIDS drug development and treatment

Background: Tacrolimus (TAC) and mycophenolic acid (MPA) are the main immunosuppressive drugs used in pediatric kidney transplantation. Single nucleotide polymorphisms (SNPs) in metabolizing enzymes and transporters might influence plasma levels of these drugs. Herein, we sought to determine the influence of SNPs on CYP3A5 , MRP2 and UGT1A9 genes in Chilean pediatric kidney recipients using TAC and MPA. Patients and Methods: A prospective study was performed on 104 pediatric kidney recipients that used TAC and MPA for immunosuppression. The median age at the time of transplantation was 8.1 years [Q1–Q3 4.5–11.6 years] and the main clinical diagnosis was a structural anomaly. In a subgroup of patients, a complete steroid withdrawal was made at day 7. The CYP3A5 polymorphism (ancestral allele *1; variant allele *3) was determined in the entire cohort, while MRP2 -24G > A, UGT1A9 -275T > A, and UGT1A9 -2152C > T polymorphisms were determined in 53 patients. Genotypes were associated with trough drug concentrations (C 0 ), dose requirements normalized by weight (TAC-D mg/kg) or body surface (MPA-D mg/m2), trough levels normalized by dose requirements (C 0 /D), and area under the curve in 12 h normalized by dose requirements (AUC 0–12h /D). Results: The frequencies of the variant alleles CYP3A5*3 , MRP2-24A , UGT1A9-275A , and UGT1A9-2152T were 76.9, 22.1, 6.6, and 2.9%, respectively. AUC 0–12h /TAC-D were 1.6-fold higher in CYP3A5*3/*3 patients than in CYP3A5...