Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
Int J Oncol. 2010 Jan;36(1):213-22.
Knowledge of the presence and extent of disease plays a major role in clinical management of prostate cancer, as it provides meaningful information as to which therapy to choose and who might benefit from this therapy. The wide expression of androgen receptor (AR) in primary and metastatic prostate tumors offers a cellular target for receptor-mediated imaging of prostate cancer. In our previous study, a non-steroidal AR ligand, S-26 [S-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-iodophenyl)-propionamide] showed promising in vitro pharmacological properties as an AR-mediated imaging agent, with high AR binding affinity and AR specificity. The overall goal of this study was to characterize the in vivo metabolic and biodistribution profile of S-26 in rats. Non-compartmental pharmacokinetic analysis of S-26 in rat plasma showed that clearance (CL), volume of distribution (Vd(ss)), and half-life (T(1/2)) of S-26 were 0.30 + or - 0.07 l/h/kg, 1.44 + or - 0.33 l/kg, and 4 h, respectively, after intravenous (i.v.) administration. Dose proportionality (1, 10 and 30 mg/kg) studies suggested that the pharmacokinetics of S-26 are dose-independent. The plasma concentrations of all 3 doses were further simultaneously fitted with a two-compartmental model and the results were similar to those obtained from non-compartmental analysis. Biodistribution studies using (125)I-labeled S-26 indicated that it did not specifically target AR-rich tissue (e.g. prostate). A substantial amount of radioactivity recovered from thyroid gland indicated the release of free iodine. In metabolism studies, unchanged S-26 and its metabolites were detected in rat urine and fecal samples. Oxidation, de-iodination, hydrolysis, and sulfate conjugation were the major metabolic pathways of S-26 in rats, with de-iodination representing a unique metabolic pathway of S-26 among other selective androgen receptor modulators. In conclusion, the extensive plasma clearance and de-iodination of S-26 likely contribute to its lack of AR tissue selectivity in vivo. Future studies using metabolically stable ligands with less lipophilicity and higher AR binding affinity may represent a promising and rational approach for AR-mediated imaging.
对疾病的存在和范围的了解在前列腺癌的临床管理中起着重要作用，因为它提供了有意义的信息，说明应该选择哪种治疗方法，以及谁可能从这种治疗中受益。雄激素受体 (AR) 在原发性和转移性前列腺肿瘤中的广泛表达为受体介导的前列腺癌成像提供了细胞靶标。在我们之前的研究中，一种非甾体 AR 配体 S-26 [S-3-(4-氟苯氧基)-2-羟基-2-甲基-N-(4-氰基-3-碘苯基)-丙酰胺] 表现出作为 AR 介导的成像剂具有有前途的体外药理学特性，具有高 AR 结合亲和力和 AR 特异性。本研究的总体目标是表征 S-26 在大鼠体内的代谢和生物分布特征。大鼠血浆中非隔室药代动力学分析表明，S-26 的清除率 (CL)、分布容积 (Vd(ss)) 和半衰期 (T(1/2)) 分别为 0.30 + 或 - 0.07 l/h/kg、1.44 + 或 - 0.33 l/kg 和 4 h，静脉注射 (i.v.) 后。剂量比例 (1、10 和 30 mg/kg) 研究表明 S-26 的药代动力学与剂量无关。所有 3 个剂量的血浆浓度进一步同时用双室模型拟合，结果与非隔室分析结果相似。使用 (125)I 标记的 S-26 的生物分布研究表明，它不能特异性靶向 AR 丰富的组织 (如前列腺)。从甲状腺中回收的大量放射性表明游离碘的释放。在代谢研究中，在大鼠尿液和粪便样本中检测到未改变的 S-26 及其代谢物。氧化、去碘、水解和硫酸结合是 S-26 在大鼠中的主要代谢途径，去碘化是 S-26 在其他选择性雄激素受体调节剂中的独特代谢途径。总之，S-26 的广泛血浆清除和去碘化可能导致其在体内缺乏 AR 组织选择性。使用脂溶性更低和 AR 结合亲和力更高的代谢稳定配体的未来研究可能代表一种有前途和合理的方法，用于 AR 介导的成像。
