Methotrexate gene polymorphisms link to toxicity but not pharmacokinetics in Chinese adults and adolescents with acute lymphoblastic leukemia.
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High-dose methotrexate (HD-MTX) is essential in treating acute lymphoblastic leukemia (ALL), but its pharmacokinetics and toxicity are influenced by transporter and metabolic enzyme gene polymorphisms. This study examines the impact of gene polymorphisms in the MTX metabolic pathway on toxicity and pharmacokinetics in Chinese patients with ALL to aid individualized therapy in order to ensure the safety of patients. We prospectively collected 273 serum MTX concentration data from 92 patients with ALL (15-71 years) undergoing HD-MTX. Differences in liver and kidney toxicity markers were analyzed across gene polymorphisms. A population pharmacokinetic model was developed using nonlinear mixed-effect modeling to explore the impact of demographic, biochemical, and genetic covariates. Patients who were homozygous for γ-glutamyl hydrolase gene rs13248452 (GG + AA genotypes) had higher urea levels. SLCO1B1 mutant allele carriers had elevated alanine aminotransferase and aspartate aminotransferase levels compared with homozygous patients. SLC19A1 rs2838957 CT genotype patients had significantly higher aspartate aminotransferase. Population pharmacokinetic analysis indicated that the glomerular filtration rate significantly affected the MTX clearance, whereas gene polymorphisms did not significantly alter the clearance rate or volume of distribution of MTX. In conclusion, gene polymorphisms in SLCO1B1, SLC19A1, and γ-glutamyl hydrolase correlate with MTX-induced alterations in liver and kidney function indicators, but the toxicity mechanisms may be independent of systemic pharmacokinetics. In clinical practice, dosage adjustments should be made based on glomerular filtration rate, with enhanced monitoring for high-risk genotypes. Genetic markers should be combined with renal function monitoring to optimize individualized MTX therapy and improve safety. SIGNIFICANCE STATEMENT: This study identifies γ-glutamyl hydrolase/SLCO1B1/SLC19A1 polymorphisms as key predictors of methotrexate toxicity in Chinese acute lymphoblastic leukemia patients, whereas population pharmacokinetic reveals glomerular filtration rate-not genetics-drives clearance. Findings advocate for genotype-toxicity monitoring and glomerular filtration rate-based dosing to improve safety.