Pharmacogenomics and Personalized Medicine (Nov 2022)
The Role of Single Nucleotide Polymorphisms in Transporter Proteins and the Folate Metabolism Pathway in Delayed Methotrexate Excretion: A Case Report and Literature Review
Abstract
Jun Wang,1 Yue-Tao Zhao,2,3 Meng-Jiao Sun,1 Feng Chen,3 Hong-Li Guo3 1Department of Hematology and Oncology, Children’s Hospital of Nanjing Medical University, Nanjing, 210008, People’s Republic of China; 2School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, 210009, People’s Republic of China; 3Pharmaceutical Sciences Research Center, Department of Pharmacy, Children’s Hospital of Nanjing Medical University, Nanjing, 210008, People’s Republic of ChinaCorrespondence: Hong-Li Guo, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing, 210008, People’s Republic of China, Email [email protected]: High-dose methotrexate (HDMTX) is a pivotal component of the chemotherapeutic regimens of osteosarcoma. However, the use of HDMTX is limited by an increased risk of dose-dependent toxicity. It is thought that the plasma levels and therapy-related toxicity of MTX could be associated with single nucleotide polymorphisms (SNPs) within MTX metabolism pathway genes. Here, we report a case of a paediatric osteosarcoma girl with delayed MTX excretion who was successfully managed using supportive measures and continuous veno-venous haemodiafiltration. We further identified the cause that could account for delayed elimination by genotyping analysis. The results showed that variations have been found in SLCO1B1, SLC19A1, ABCB1 and MTHFR, all those were reported to have a strong association with delayed elimination of MTX in clinical studies. After comprehensive consideration of genotype and clinical phenotype, the second course of HDMTX was administered to this patient at a half reduced dose. We also performed a literature review to summarize the pharmacogenetic factors that influence HDMTX pharmacokinetics or MTX-related adverse effects in osteosarcoma patients. It is suggested that the potential risk of delayed MTX elimination is worthy of clinical attention, and the implementation of genotyping should be considered to ensure therapeutic safety.Graphical Abstract: Keywords: high-dose methotrexate, osteosarcoma, delayed excretion, single nucleotide polymorphisms
