Tocco D J, Hooke K F, Deluna F A, Duncan A E
Drug Metab Dispos. 1976 Jul-Aug;4(4):323-9.
The beta-adrenergic blocking agent, timolol, appears to be bound to stereospecific as well as nonspecific sites in the particulate fraction (8500g pellet) of the heart, lungs, and brain, whereas the d-isomer of timolol was bound to nonspecific sites only. Timolol disappeared from the particulate fraction at a slower rate than did its optical isomer. At 1 hr after a 0.1-mg/kg dose, the concentration of the l-form in the lung was 1.8 times that of the d-isomer and at 3 and 4 hr the difference was at least 33-fold. The concentration of 14C-timolol in the particulate fraction of rat tissues was inhibited by iv administered timolol and by the l-isomer of propanolol, but not by their corresponding d-forms. Competition for binding sites was dose dependent. Pretreatment with timolol at 0.1 and 5.0 mg/kg reduced the binding of 14C-timolol (dose, 0.1 mg/kg) to lung tissue by 41% and 86%, respectively. In the heart and lung tissue of rats, racemic timolol, propranolol, bunolol, and bunitrolol were approximately equally effective in competing for the binding sites of 14C-timolol. Practolol and sotalol and the beta 2-selective agent butoxamine did not significantly inhibit the binding of 14C-timolol. Similar competition was also observed in the whole brain of rats. This report suggests that the stereospecific binding of timolol may be related to the beta-adrenoreceptor process.
β-肾上腺素能阻滞剂噻吗洛尔似乎与心脏、肺和脑的微粒体部分（8500g沉淀）中的立体特异性以及非特异性位点结合，而噻吗洛尔的d-异构体仅与非特异性位点结合。噻吗洛尔从微粒体部分消失的速率比其光学异构体慢。在给予0.1mg/kg剂量1小时后，肺中l-型的浓度是d-异构体的1.8倍，在3小时和4小时时，差异至少为33倍。静脉注射噻吗洛尔和普萘洛尔的l-异构体可抑制大鼠组织微粒体部分中14C-噻吗洛尔的浓度，但其相应的d-型则无此作用。对结合位点的竞争呈剂量依赖性。以0.1mg/kg和5.0mg/kg的噻吗洛尔预处理分别使14C-噻吗洛尔（剂量为0.1mg/kg）与肺组织的结合减少了41%和86%。在大鼠的心脏和肺组织中，消旋噻吗洛尔、普萘洛尔、布诺洛尔和丁呋洛尔在竞争14C-噻吗洛尔的结合位点方面效果大致相同。醋丁洛尔、索他洛尔和β2-选择性药物布托沙明并未显著抑制14C-噻吗洛尔的结合。在大鼠全脑中也观察到了类似的竞争情况。本报告表明，噻吗洛尔的立体特异性结合可能与β-肾上腺素受体过程有关。
