Stereoselective delivery and actions of beta receptor antagonists.
Stereoselective delivery and actions of beta receptor antagonists.
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β 受体拮抗剂的立体选择性递送和作用。
DOI：
10.1016/0006-2952(88)90763-0
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发表时间：
1988
影响因子：
5.8
通讯作者：
Gaffney,TE
中科院分区：
文献类型：
--
作者：
Walle,T;Webb,JG;Bagwell,EE;Walle,UK;Daniell,HB;Gaffney,TE
这些研究表明，β受体拮抗剂药物的递送和作用是由涉及多种酶、转运蛋白和受体的一系列立体选择性过程控制的。本质上，呈递给细胞表面β受体的这些药物的药理活性(-)-对映体种类的游离浓度似乎是肝细胞色素P-450同工酶、对映体选择性结合α1-酸性糖蛋白和白蛋白的立体选择性清除的函数，并且可能主要通过肾上腺素能神经元内的囊泡胺转运蛋白的立体选择性封存（和释放）。 β 阻断药物可能有利于 (+)- 或 (−)- 对映体，似乎仅对通过肝脏代谢清除的亲脂性药物很重要。这种立体选择性是由于各个肝细胞色素 P-450 同工酶的立体化学底物需求不同所致。由于遗传倾向或其他因素，细胞色素 P-450 同工酶的数量和表达存在差异，从而可能导致立体选择性的个体间差异。在同一背景下，我们观察到β阻断药物与血浆蛋白结合的程度和立体选择性之间存在显着相关性。这是另一项发现，表明参与β阻断药物-蛋白质级联的各个蛋白质表达的变异性决定了药理活性对映体的游离浓度。然而，由于大多数观察是在年轻的正常受试者中进行的，因此在一般人群中，代谢、结合和其他过程中的立体选择性程度尚不清楚，因为多种生物因素，稳态血浆浓度可能变化很大。神经研究的观察结果支持这样的概念，即肾上腺素能神经末梢为β受体拮抗剂的活性对映体的立体选择性储存和释放提供了一个库。这种释放的机制似乎涉及由神经递质储存囊泡立体选择性积累的药物的胞吐分泌。根据这个想法，在神经刺激过程中释放的β受体拮抗剂可能会在肾上腺素能突触内达到大大超过血浆中发现的浓度的(-)-对映体。这种机制可以显着影响心脏、血管、大脑和其他靶组织中β受体阻断的强度和持续时间。事实上，在药物的血浆水平明显下降到有效浓度以下后，β受体拮抗剂的心血管作用持续存在，这可以部分地用这种现象来解释。无论如何，很明显，神经末梢的立体选择性储存和分泌提供了一种额外的机制，用于调节β受体阻断药物的活性对映体在肾上腺素突触内的作用位点的递送和浓度。 总之，多种酶、转运蛋白和其他蛋白质，每种都具有特定的立体化学要求，决定了β受体拮抗剂药物的递送和治疗作用。
These studies have revealed that the delivery and actions of beta receptor antagonist drugs are controlled by a cascade of stereoselective processes involving multiple enzymes, transport proteins and receptors. In essence, the free concentration of the pharmacologically active (−)-enantiomer species of these drugs presented to cell surface beta receptors appears to be a function of the stereoselective clearance by hepatic cytochrome P-450 isoenzymes, enantiomer selective binding to α1-acid glycoprotein and albumin and perhaps predominantly by stereoselective sequestration (and release) by the vesicular amine transport protein within adrenergic neurons.Stereoselectivity in the clearance of beta blocking drugs, which can favor either the (+)- or (−)- enantiomer, only appears to be important for the lipophilic drugs which are cleared by hepatic metabolism. Such Stereoselectivity is due to differential stereochemical substrate requirements of individual hepatic cytochrome P-450 isoenzymes. Interindividual variations in the Stereoselectivity can occur as a result of differences in the amount and expression of cytochrome P-450 isoenzymes due to genetic predisposition or other factors. In the same context, we have observed a significant correlation between the extent and Stereoselectivity of binding of beta blocking drugs to plasma proteins. This is another finding which suggests that variability in the expression of individual proteins involved in the beta blocking drug-protein cascade determines the free concentration of the pharmacologically active enantiomer. However, since most observations have been made in young normal subjects, the extent of Stereoselectivity in metabolism, binding and other processes is unknown in the general population where steady-state plasma concentrations can vary widely due to multiple biological factors.The observations from neural studies support the concept that adrenergic nerve endings provide a depot for the stereoselective storage and release of the active enantiomer of beta receptor antagonists. The mechanism of this release appears to involve exocytotic secretion of drug that has been stereoselectively accumulated by the neurotransmitter storage vesicles. In terms of this idea, beta receptor antagonists released during nerve stimulation may achieve concentrations of the (−)-enantiomer within the adrenergic synapse greatly in excess of those found in plasma. Such a mechanism could significantly influence both the intensity and duration of beta receptor blockade in the heart, blood vessels, brain and other target tissues. Indeed, persistence of the cardiovascular effects of beta receptor antagonists after plasma levels of drug have apparently declined below effective concentrations could be explained in part by this phenomenon. In any event, it seems clear that stereoselective storage and secretion by nerve endings provides an additional mechanism for modulating the delivery and concentration of the active enantiomer of beta receptor blocking drugs at sites of action within the adrenergic synapse.In conclusion, multiple enzymes, transport proteins and other proteins, each with specific stereochemical requirements, determine the delivery and therapeutic actions of beta receptor antagonist drugs.
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不同物种在体外对 4-羟基普萘洛尔进行立体选择性硫酸盐缀合。
DOI：
--
发表时间：
1985
期刊：
Drug metabolism and disposition: the biological fate of chemicals
影响因子：
--
作者：
Christ,DD;Walle,T
通讯作者：
Walle,T
大鼠大脑皮层突触体中普萘洛尔的积累、亚细胞定位和释放。
DOI：
--
发表时间：
1984
期刊：
The Journal of pharmacology and experimental therapeutics
影响因子：
--
作者：
Street,JA;Webb,JG;Bright,PS;Gaffney,TE
通讯作者：
Gaffney,TE
β-肾上腺素能阻断剂 (l-)-1-叔丁基氨基-3-(2,3-二甲基苯氧基)-2-丙醇盐酸盐（盐酸希苯洛尔，D-32）在人体代谢中的立体选择性。
影响因子：
1.7
作者：
S. Honma;T. Ito;A. Kambegawa
通讯作者：
A. Kambegawa
给予人外消旋(i-)-普萘洛尔后，()和(-)-普萘洛尔以及4-羟基普萘洛尔的血浆水平。
影响因子：
3.4
作者：
C. von Bahr;J. Hermansson;K. Tawara
通讯作者：
K. Tawara
血浆普萘洛尔水平在人体 β-肾上腺素能阻断定量评估中的应用
影响因子：
--
作者：
D. Coltart;D. Shand
通讯作者：
D. Shand