Figure 1
Methotrexate pathway and related pharmacogenomics. (A) This figure illustrates Methotrexate (MTX) pharmacokinetics, subject to genetic variations in membrane transporter proteins. MTX absorption in the gastrointestinal tract involves SLC19A1 and SLC46A1, while ABC transporters impact oral dosing bioavailability. Intravenous administration, prevalent in hematologic malignancy protocols, bypasses gastrointestinal transporters, ensuring heightened bioavailability. As kidneys are the primary excretory organs for MTX, the potential for kidney injury is influenced by genomic variations and patient-specific factors, underscoring the importance of understanding these intricacies in MTX pharmacokinetics. (B) This figure summarizes the complexity of the MTX pathway, purine synthesis, pyrimidine synthesis, folate metabolism, and related downstream target genes. These genomic variations resulted in the alteration of MTX level in the cellular level; thus, it might lead to clinical outcomes. MTX mainly inhibits DHFR, TYMS, PPAT, GART, and ATIC leading to cell apoptosis, especially in high turnover rate cells like cancer cells. The variant of MTRR gene allele rs1801394, which was significantly associated with acute kidney injury in this study, has its main action in changing from homocysteine to methionine. The effect of this variant in the alteration of cellular substrate has not been well-established to our understanding. This figure has been modified from the pharmacogenomics study from PharmGKB®29,30and created with BioRender.com. MTX methotrexate, DHF dihydrofolate, THF trihydrofolate, IMP inosine monophosphate, AMP adenosine monophosphate, ADP adenosine diphosphate, ATP adenosine triphosphate, dUMP deoxyuridine monophosphate, dTMP deoxythymidine monophosphate, SAM S-adenosyl methionine, SAH S-adenosyl homocysteine.
