Influence of TPMT and NUDT15 Genetic Polymorphisms on Mercaptopurine Pharmacokinetics in Healthy Volunteers.

This study aimed to investigate the impact of genetic polymorphisms of thiopurine methyltransferase (TPMT) and NUDT15 on pharmacokinetics profile of mercaptopurine in healthy adults in China. Blood samples were obtained from 45 healthy adult volunteers who were administered azathioprine. Genomic DNA was extracted and sequenced for TPMT and NUDT15. The plasma concentrations of 6-mercaptopurine (6-MP) were determined by ultra-performance liquid chromatography-tandem mass spectrometry. Finally, pharmacokinetic parameters were calculated based on the time-concentration curve. Among the 45 healthy adult volunteers enrolled in the study, two TPMT allelic variants and three NUDT15 allelic variants were detected. In total, six genotypes were identified, including , , , and . The results indicated that Area Under Curve (AUC) of 6-MP in volunteers with TPMT*1/3&NUDT151/2 and TPMT1/6&NUDT151/2 were 1.57-1.62-fold higher than in individuals carrying the wild type (TPMT1/1&NUDT151/*1). Compared with wild type, the half-life (T) of was extended by 1.98 times, whereas T of decreased by 67%. The maximum concentration (C) of increased significantly by 2.15-fold, whereas the corresponding clearance (CL/F) decreased significantly by 58.75%. The findings of this study corroborate the notion that various genotypes of TPMT and NUDT15 can impact the pharmacokinetics of mercaptopurine, potentially offering foundational insights for personalized mercaptopurine therapy.