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. 2022 Mar 17:14:17588359221081075.
doi: 10.1177/17588359221081075. eCollection 2022.

Influence of probenecid on endoxifen systemic exposure in breast cancer patients on adjuvant tamoxifen treatment

Stefan A J Buck  1 , C Louwrens Braal  2 , Maaike M Hofman  2 , Esther Oomen-de Hoop  2 , Peter de Bruijn  2 , Inge M Ghobadi Moghaddam-Helmantel  2 , Koen G A M Hussaarts  2 , Mijntje B Vastbinder  3 , Quirine C van Rossum-Schornagel  4 , Ron H N van Schaik  5 , Agnes Jager  2 , Stijn L W Koolen  6 , Ron H J Mathijssen  2
Affiliations

Influence of probenecid on endoxifen systemic exposure in breast cancer patients on adjuvant tamoxifen treatment

Stefan A J Buck et al. Ther Adv Med Oncol. .

Abstract

Introduction: In breast cancer patients treated with the anti-estrogen tamoxifen, low concentrations of the active metabolite endoxifen are associated with more disease recurrence. We hypothesized that we could increase endoxifen concentrations by induction of its formation and inhibition of its metabolism by co-administration of probenecid.

Methods: We conducted a crossover study and measured endoxifen concentrations in patients on steady-state tamoxifen monotherapy and after 14 days of combination treatment with probenecid. Eleven evaluable patients were included.

Results: Treatment with tamoxifen and probenecid resulted in a 26% increase of endoxifen area under the plasma concentration-time curve from 0 to 24 h (AUC0-24h) compared to tamoxifen monotherapy (95% confidence interval [CI]: 8-46%; p < 0.01), while the maximum observed endoxifen concentration increased with 24% (95% CI: 7-44%; p < 0.01). The metabolic ratio of endoxifen to tamoxifen increased with 110% (95% CI: 82-143%; p < 0.001) after the addition of probenecid.

Conclusion: Probenecid resulted in a clinically relevant increase of endoxifen concentrations in breast cancer patients treated with adjuvant tamoxifen. This combination therapy could provide a solution for patients with a CYP2D6-poor metabolizer phenotype or endoxifen concentrations below the threshold despite earlier tamoxifen dose.

Keywords: breast cancer; endoxifen; metabolism; probenecid; tamoxifen.

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Conflict of interest statement

Conflict of interest statement: The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Figures

Figure 1.
Figure 1.
Tamoxifen metabolism and hypothesized mechanism of CYP3A4 induction and UGT inhibition by probenecid. After administration, tamoxifen is metabolized to N-desmethyl-tamoxifen and 4-hydroxy-tamoxifen, mainly by CYP3A4 and CYP2D6, respectively. Next, N-desmethyl-tamoxifen and 4-hydroxy-tamoxifen are metabolized to endoxifen, mainly by CYP2D6 and CYP3A4, respectively. Endoxifen gets glucuronidated by UGTs to the inactive endoxifen-glucuronide. CYP, cytochrome P450; UGT, UDP-glucuronosyltransferase.
Figure 2.
Figure 2.
Plasma concentrations of endoxifen and tamoxifen with and without probenecid. Geometric mean plasma concentration vs time profiles of endoxifen (a) and dose-corrected tamoxifen (b) are shown for tamoxifen monotherapy (blue) and tamoxifen with probenecid combination therapy (red). Confidence bands indicate the 95% CI (n = 11).
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