Dynamics and Metabolism, Worldwide Research and Development, Pfizer, Inc, San Diego, California, United States of America.
PLoS One. 2012;7(9):e44359. doi: 10.1371/journal.pone.0044359. Epub 2012 Sep 6.
A systems-level mathematical model is presented that describes the effects of inhibiting the enzyme 5α-reductase (5aR) on the ventral prostate of the adult male rat under chronic administration of the 5aR inhibitor, finasteride. 5aR is essential for androgen regulation in males, both in normal conditions and disease states. The hormone kinetics and downstream effects on reproductive organs associated with perturbing androgen regulation are complex and not necessarily intuitive. Inhibition of 5aR decreases the metabolism of testosterone (T) to the potent androgen 5α-dihydrotestosterone (DHT). This results in decreased cell proliferation, fluid production and 5aR expression as well as increased apoptosis in the ventral prostate. These regulatory changes collectively result in decreased prostate size and function, which can be beneficial to men suffering from benign prostatic hyperplasia (BPH) and could play a role in prostate cancer. There are two distinct isoforms of 5aR in male humans and rats, and thus developing a 5aR inhibitor is a challenging pursuit. Several inhibitors are on the market for treatment of BPH, including finasteride and dutasteride. In this effort, comparisons of simulated vs. experimental T and DHT levels and prostate size are depicted, demonstrating the model accurately described an approximate 77% decrease in prostate size and nearly complete depletion of prostatic DHT following 21 days of daily finasteride dosing in rats. This implies T alone is not capable of maintaining a normal prostate size. Further model analysis suggests the possibility of alternative dosing strategies resulting in similar or greater effects on prostate size, due to complex kinetics between T, DHT and gene occupancy. With appropriate scaling and parameterization for humans, this model provides a multiscale modeling platform for drug discovery teams to test and generate hypotheses about drugging strategies for indications like BPH and prostate cancer, such as compound binding properties, dosing regimens, and target validation.
提出了一个系统水平的数学模型，描述了在成年雄性大鼠的慢性给予 5α-还原酶（5aR）抑制剂非那雄胺的情况下，抑制酶 5aR 对其前列腺腹侧叶的影响。5aR 在雄性的正常和疾病状态下对雄激素的调节都是必不可少的。激素动力学和扰乱雄激素调节对生殖器官的下游影响是复杂的，并不一定是直观的。5aR 的抑制减少了睾酮（T）向强效雄激素 5α-二氢睾酮（DHT）的代谢。这导致前列腺腹侧叶中的细胞增殖、液体产生和 5aR 表达减少以及细胞凋亡增加。这些调节变化共同导致前列腺体积和功能的降低，这对患有良性前列腺增生（BPH）的男性有益，并且可能在前列腺癌中发挥作用。在男性和大鼠中有两种不同的 5aR 同工型，因此开发 5aR 抑制剂是一项具有挑战性的工作。有几种 5aR 抑制剂用于治疗 BPH，包括非那雄胺和度他雄胺。在这项研究中，模拟与实验 T 和 DHT 水平和前列腺体积的比较表明，该模型准确地描述了在大鼠中每天给予非那雄胺 21 天后前列腺体积约减少 77%，并且前列腺 DHT 几乎完全耗尽。这意味着 T 单独不能维持正常的前列腺体积。进一步的模型分析表明，由于 T、DHT 和基因占据之间的复杂动力学，可能存在替代给药策略，从而对前列腺体积产生相似或更大的影响。通过适当的缩放和参数化用于人类，该模型为药物发现团队提供了一个多尺度建模平台，用于测试和生成关于 BPH 和前列腺癌等适应症的药物策略的假设，例如化合物结合特性、给药方案和靶标验证。
