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Background and Objectives <p>Doxorubicin (DOX) and its metabolite doxorubicinol (DOXol) are drugs with large differences in pharmacokinetics (PK) between patients. In this study, we investigated the effects of polymorphisms in PK-related genes on the areas under the plasma concentration-time curves (AUCs) of DOX and DOXol.</p> Methods <p>This study included 43 patients diagnosed with non-Hodgkin lymphoma undergoing the first round of CHOP therapy. The AUCs of DOX and DOXol were calculated using the linear trapezoidal rule based on the plasma concentrations in blood sampled from 1.5 to 25.5 h after the start of administration. Genotyping was performed for genes encoding carbonyl reductase (<i>CBR1</i>, <i>CBR3</i>), aldo-keto reductase (<i>AKR1C3</i>), and transporters (<i>ABCB1</i>, <i>ABCG2</i>).</p> Results <p>Although the dose of DOX was adjusted for body surface area for each patient, the coefficients of variation for the AUCs of DOX and DOXol were substantial. Serum albumin was identified as an independent factor significantly influencing the dose-adjusted AUC of DOX (AUC/D; <i>R</i><sup>2</sup> = 0.116,<i> P</i> = 0.015). Additionally, body mass index was identified as an independent factor significantly influencing the AUC/D of DOXol and the DOX-DOXol AUC ratio (DOXol/DOX; <i>R</i><sup>2</sup> = 0.181, <i>P</i> = 0.003 and <i>R</i><sup>2</sup> = 0.134, <i>P</i> = 0.009, respectively). Nonetheless, no significant differences in PK parameters were observed among polymorphisms in PK-related genes.</p> Conclusions <p>Our findings suggested that polymorphisms in <i>CBR1</i>, <i>CBR3</i>, <i>AKR1C3</i>, <i>ABCB1</i>, and <i>ABCG2</i> were unlikely to be reliable predictors of cumulative plasma exposure to DOX and DOXol. Therefore, mitigating the risk of cumulative plasma exposure to DOX and DOXol through PK approaches may require the development of novel therapeutic drug monitoring strategies.</p> <p><MediaObject ID="MOESM1"> <VideoObject FileRef="MediaObjects/13318_2025_940_MOESM1_ESM.mp4" VideoID="9JPzNGmUojZvzwJ4o4ozxD"> <Caption Language="En" xml:lang="en"> <CaptionContent> <p>Supplementary file1 (MP4 3804 KB)</p> </CaptionContent> </Caption> </VideoObject> </MediaObject></p>

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Influence of Polymorphisms in Pharmacokinetics-Related Genes on the Areas Under the Plasma Concentration-Time Curves of Doxorubicin and Doxorubicinol in Patients with Diffuse Large B-Cell Lymphoma Receiving CHOP Therapy

  • 期刊论文

  • 发表日期：

    2025年4月4日

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  • Keigo Saito,
  • Takenori Takahata,
  • Junichi Nakagawa,
  • Yu Chen,
  • Kensuke Saito,
  • Kosuke Kamata,
  • Takuto Tachita,
  • Satoru Yamashita,
  • Kayo Ueno,
  • Atsushi Sato,
  • Hirotake Sakuraba,
  • Takenori Niioka

摘要

Background and Objectives

Doxorubicin (DOX) and its metabolite doxorubicinol (DOXol) are drugs with large differences in pharmacokinetics (PK) between patients. In this study, we investigated the effects of polymorphisms in PK-related genes on the areas under the plasma concentration-time curves (AUCs) of DOX and DOXol.

Methods

This study included 43 patients diagnosed with non-Hodgkin lymphoma undergoing the first round of CHOP therapy. The AUCs of DOX and DOXol were calculated using the linear trapezoidal rule based on the plasma concentrations in blood sampled from 1.5 to 25.5 h after the start of administration. Genotyping was performed for genes encoding carbonyl reductase (CBR1, CBR3), aldo-keto reductase (AKR1C3), and transporters (ABCB1, ABCG2).

Results

Although the dose of DOX was adjusted for body surface area for each patient, the coefficients of variation for the AUCs of DOX and DOXol were substantial. Serum albumin was identified as an independent factor significantly influencing the dose-adjusted AUC of DOX (AUC/D; R2 = 0.116, P = 0.015). Additionally, body mass index was identified as an independent factor significantly influencing the AUC/D of DOXol and the DOX-DOXol AUC ratio (DOXol/DOX; R2 = 0.181, P = 0.003 and R2 = 0.134, P = 0.009, respectively). Nonetheless, no significant differences in PK parameters were observed among polymorphisms in PK-related genes.

Conclusions

Our findings suggested that polymorphisms in CBR1, CBR3, AKR1C3, ABCB1, and ABCG2 were unlikely to be reliable predictors of cumulative plasma exposure to DOX and DOXol. Therefore, mitigating the risk of cumulative plasma exposure to DOX and DOXol through PK approaches may require the development of novel therapeutic drug monitoring strategies.

Supplementary file1 (MP4 3804 KB)