To investigate whether the CYP1A2 genetic polymorphisms could affect the pharmacokinetics of pentoxifylline and its two active metabolites in Chinese healthy participants. Forty-six healthy Chinese volunteers were administered a single 400 mg oral dose of pentoxifylline. The plasma concentrations of pentoxifylline and its active metabolites were quantified using LC-MS/MS. The CYP1A2 genotypes for the following loci were determined by the SnapShot technique: -5347T > C (rs2470890), -3860G > A (rs2069514), -3594T > G (rs2069520), -3113 C > A (rs2069521), -2467delT (rs35694136), -739T > G (rs2069526), -163 C > A (rs762551), and 2159G > A (rs2472304). Participants heterozygous for the CYP1A2 -3860G/A genotype exhibited a 22.3% and 17.6% reduction in the Cmax of metabolite M5 compared to homozygous − 3860G/G and − 3860 A/A carriers, respectively. Participants carrying the CYP1A2 -3860G/A genotype exhibited reduced AUC0–t and AUC0–∞ values of metabolite M5 compared to both homozygous − 3860G/G and − 3860 A/A carriers. Additionally, participants with the CYP1A2 -163 C/A genotype had significantly lower pentoxifylline AUC0–t and AUC0–∞ than those with the − 163 C/C genotype (reduced by 29.14% and 28.62%, respectively). In contrast, no significant differences were observed in the pharmacokinetic parameters of the primary metabolites M1 and M5 across the different CYP1A2 genotype groups. The two CYP1A2 polymorphisms significantly affected pharmacokinetics: the − 3860G > A variant was associated with a significant reduction in systemic exposure to metabolite M5, while potentially increasing exposure to pentoxifylline and M1. Conversely, the − 163 C > A variant significantly reduced the plasma exposure of the parent drug pentoxifylline, with a trend toward decreased exposure for metabolites M1 and M5. This clinical trial has been registered in the Chinese Clinical Trial Register (accessible at http://www.chinadrugtrials.org.cn/index.htmL) with the registration number CTR20233180 on October 08, 2023.
Guo et al. (Thu,) studied this question.