Purpose To investigate whether the CYP1A2 genetic polymorphisms could affect the pharmacokinetics of pentoxifylline and its two active metabolites in Chinese healthy participants. Methods 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). Results 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. Conclusions 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. Trial registration This clinical trial has been registered in the Chinese Clinical Trial Register (accessible at <a href="http://www.chinadrugtrials.org.cn/index.htmL">http://www.chinadrugtrials.org.cn/index.htmL</a>) with the registration number CTR20233180 on October 08, 2023.

Effects of CYP1A2 genetic polymorphisms on the pharmacokinetics of pentoxifylline and its active metabolites

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2026年2月26日

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Lingfang Guo,
Xue Sun,
Bo Qiu,
Wanjun Bai,
Yabin Du,
Haojing Song

摘要

Purpose

To investigate whether the CYP1A2 genetic polymorphisms could affect the pharmacokinetics of pentoxifylline and its two active metabolites in Chinese healthy participants.

Methods

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).

Results

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 AUC_0–t and AUC_0–∞ 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 AUC_0–t and AUC_0–∞ 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.

Conclusions

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.

Trial registration

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.