Background Tamoxifen (TAM), a selective modulator of estrogen receptors (SERMs) has been recently explored as a therapeutic option for the oral treatment of airway inflammation in the horse. The objective of this work was to establish pharmacokinetic parameters of TAM and its main metabolites in equines, as well as to determine its clinical safety in short-term treatments. Results We determined TAM and its three main metabolites (4-OH tamoxifen, endoxifen, and N-desmethyl tamoxifen) in plasma after single administration of 0.25 mg/kg in healthy adult horses (n = 12). A maximum concentration of TAM was achieved 3 h after the oral administration (4.65 pg/mL ± 1.69); 4-OH tamoxifen was the metabolite that reached the highest concentration (78 pg/mL ± 70), followed by N-desmethyl tamoxifen (0.43 pg / mL ± 0.48), and finally endoxifen (0.17 pg/mL ± 0.17). All metabolites showed peak concentration 2 h after oral administration of the drug. Oral TAM bioavailability was 13,15% ± 4,18, with a steady state volume of distribution of 7831 ± 2922 (L/kg). Elimination half-life was 15.40 ± 5.80 h, and clearance was 5876 ± 699 (mL/kg/min). Clinical safety of TAM was determined over a 7-day course of treatment (0.25 mg/kg, orally q 24 h, n = 20). No adverse effects were observed through clinical examination, blood hematology, serum biochemistry, ophthalmological and reproductive examinations. Endometrial edema observed in some mares was attributed to normal cyclic activity. Conclusions Tamoxifen has moderate oral bioavailability and a large volume of distribution, with three main metabolites in horses. Additionally, oral TAM administration over a 7-day treatment period demonstrated to be clinically safe, without adverse effects on clinical, hematological or serum biochemical parameters. These data could contribute to the continued research into this drug's potential for the treatment of different inflammatory conditions in equine species.

中文翻译：

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马他莫昔芬：药代动力学和安全性研究。

背景 他莫昔芬 (TAM) 是一种雌激素受体 (SERM) 的选择性调节剂，最近已被探索作为口服治疗马气道炎症的治疗选择。这项工作的目的是建立 TAM 及其在马中的主要代谢物的药代动力学参数，并确定其在短期治疗中的临床安全性。结果 我们在健康成年马 (n = 12) 中单次给药 0.25 mg/kg 后测定了血浆中的 TAM 及其三种主要代谢物（4-OH tamoxifen、endoxifen 和 N-desmethyl tamoxifen）。口服给药后 3 小时达到 TAM 的最大浓度（4.65 pg/mL ± 1.69）；4-OH 他莫昔芬是达到最高浓度的代谢物 (78 pg/mL ± 70)，其次是 N-去甲基他莫昔芬 (0.43 pg/mL ± 0.48)，最后是内多昔芬 (0.17 pg/mL ± 0. 17). 所有代谢物在口服药物后 2 小时均出现峰值浓度。口服 TAM 生物利用度为 13.15% ± 4.18，稳态分布容积为 7831 ± 2922 (L/kg)。消除半衰期为 15.40 ± 5.80 h，清除率为 5876 ± 699 (mL/kg/min)。TAM 的临床安全性在 7 天的治疗过程中确定（0.25 mg/kg，每 24 小时口服一次，n = 20）。经临床检查、血液学、血清生化、眼科及生殖检查未见不良反应。在一些母马中观察到的子宫内膜水肿归因于正常的周期性活动。结论 他莫昔芬具有中等的口服生物利用度和大的分布容积，在马体内具有三种主要代谢物。此外，在 7 天的治疗期内口服 TAM 被证明是临床安全的，对临床、血液学或血清生化参数无不良影响。这些数据可能有助于继续研究这种药物治疗马种不同炎症状况的潜力。