Prediction of α1-adrenoceptor occupancy in the human prostate from plasma concentrations of silodosin, tamsulosin and terazosin to treat urinary obstruction in benign prostatic hyperplasia
Prediction of α1-adrenoceptor occupancy in the human prostate from plasma concentrations of silodosin, tamsulosin and terazosin to treat urinary obstruction in benign prostatic hyperplasia
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DOI：
10.1248/bpb.30.1237
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发表时间：
2007-07-01
影响因子：
2
通讯作者：
Kawabe, Kazuki
中科院分区：
文献类型：
--
作者：
Yamada, Shizuo;Kato, Yasuhiro;Kawabe, Kazuki
α（1）-肾上腺素受体拮抗剂在临床上可用于改善由良性前列腺增生（BPH）引起的尿路梗阻，并且它们的治疗效果是通过阻断前列腺μ（1-）肾上腺素受体来介导的。本研究旨在预测口服mu（1）-肾上腺素受体拮抗剂后人前列腺α-肾上腺素受体占据的幅度和持续时间。通过测量口服西洛多辛后大鼠前列腺中[H-3]哌唑嗪的特异性结合来估计西洛多辛的前列腺α（1）-肾上腺素受体结合参数。采用高效液相色谱法测定大鼠和健康志愿者口服西洛多辛后的血浆浓度。从文献中获得了人前列腺中西洛多辛、坦索罗辛和特拉唑嗪的α（1）-肾上腺素受体结合亲和力（K-i）以及坦索罗辛和特拉唑嗪的血浆浓度。使用大鼠前列腺中西洛多辛的α（1）-肾上腺素受体结合参数，估计在口服3.0、8.1和16.1 μ mol剂量的西洛多辛后1 -6小时，人前列腺中的α（1）-肾上腺素受体占有率约为60-70%。此后，受体占有率周期性下降，至24%（8.1 μ mol）和54%（16.1 μ mol）24小时后。使用人前列腺中的α（1）-肾上腺素受体结合亲和力（Ki）估计人前列腺中西洛多辛对α（1）-肾上腺素受体占用的类似幅度和时间过程。尽管在临床有效口服剂量的西洛多辛、坦索罗辛和特拉唑嗪后，血浆未结合浓度有大约两个数量级的差异，但这些药物对前列腺α（1）-肾上腺素受体的占用量相当。总之，μ 1-肾上腺素受体拮抗剂对人前列腺α 1-肾上腺素受体占有率的预测可能为这些药物治疗BPH的最佳剂量方案提供理论依据。
alpha(1)-Adrenoceptor antagonists are clinically useful for the improvement of urinary obstruction due to benign prostatic hyperplasia (BPH), and their therapeutic effects are mediated through the blockade of prostatic mu(1-)adrenoceptors. The present study was undertaken to predict the magnitude and duration of alpha-adrenoceptor occupancy in the human prostate after oral mu(1)-adrenoceptor antagonists. Prostatic alpha(1)-adrenoceptor-binding parameters of silodosin were estimated by measuring specific [H-3]prazosin binding in rat prostate after oral administration of this drug. The plasma concentration of silodosin after oral administration in rats and healthy volunteers was measured using a high-performance liquid chromatographic method. The alpha(1)-adrenoceptor-binding affinities (K-i) of silodosin, tamsulosin, and terazosin in the human prostate and plasma concentrations of tamsulosin and terazosin were obtained from the literature. Using the alpha(1)-adrenoceptor binding parameters of silodosin in rat prostates alpha(1)-adrenoceptor occupancy in the human prostate was estimated to be around 60-70% at I-6 h after oral administration of silodosin at doses of 3.0, 8.1, and 16.1 mu mol. Thereafter, the receptor occupancy was periodically decreased, to 24% (8.1 mu mol) and 54% (16.1 mu mol) 24 h later. A similar magnitude and time course of alpha(1)-adrenoceptor occupancy by silodosin in the human prostate were estimated using alpha(1)-adrenoceptor-binding affinities (K-i) in the human prostate. Despite about two orders of differences in the plasma unbound concentrations after clinically effective oral dosages of silodosin, tamsulosin, and terazosin, there was a comparable magnitude of prostatic alpha(1)-adrenoceptor occupancy by these drugs. In conclusion, the prediction of alpha(1)-adrenoceptor occupancy in the human prostate by mu(1)-adrenoceptor antagonists may provide the rationale for the optimum dosage regimen of these drugs in the therapy of BPH.