Stereoselective ring oxidation of propranolol in man.
Stereoselective ring oxidation of propranolol in man.
复制标题
人体内普萘洛尔的立体选择性环氧化。
DOI：
10.1111/j.1365-2125.1984.tb02537.x
复制
发表时间：
1984
影响因子：
3.4
通讯作者：
Gaffney,TE
中科院分区：
文献类型：
--
作者：
Walle,T;Walle,UK;Wilson,MJ;Fagan,TC;Gaffney,TE
本研究的目的是阐明人体普萘洛尔代谢的立体选择性机制。5名正常人口服80 mg氘标记的普萘洛尔假羧酸盐，采用气相色谱-质谱联用法测定其尿液中普萘洛尔及其主要代谢物的立体化学组成。未改变的心得安的（‐）/(+)‐对映体比值为1.50 +/‐0.10（平均值+/‐s.e.平均值），心得安葡萄糖醛酸酯为1.76 +/‐0.10，与之前在血浆中的发现相似。所有侧链氧化产物也主要由（‐）‐对映体组成，总体（‐）/(+)比为1.61 +/‐0.11。4 -羟基普萘洛尔的A（‐）/(+)比值为1.04 +/‐0.17，不表明环氧化具有立体选择性。然而，葡萄糖醛酸缀合物的比率为1.78 +/‐0.19，硫酸盐缀合物的比率为0.27 +/‐0.03，表明4 -羟基心得安的葡萄糖醛酸化或硫酸化或两者都有立体选择性。当考虑到这些二级途径中的立体选择性时，总的环氧化非常有利于（+）‐心得安，（‐）/(+)‐对映体比为0.59 +/‐0.09。对人体内心得安代谢的立体化学综合观察结果与（+）‐心得安的立体选择性环氧化一致，导致药理学上更有效的（‐）‐心得安具有更高的生物利用度，并导致该对映体的优先侧链氧化和糖醛酸化。
The objective of this study was to elucidate stereoselective mechanisms of propranolol metabolism in man. Five normal subjects were given single 80 mg oral doses of deuterium‐labeled pseudoracemates of propranolol, and the stereochemical composition of propranolol and its major metabolites in urine was determined by GC/MS. The (‐)/(+)‐ enantiomer ratios for unchanged propranolol, 1.50 +/‐ 0.10 (mean +/‐ s.e. mean), and propranolol glucuronide, 1.76 +/‐ 0.10, were similar to previous findings in plasma. All products of side‐chain oxidation also consisted mainly of the (‐)‐enantiomer, with an overall (‐)/(+) ratio of 1.61 +/‐ 0.11. A (‐)/(+) ratio of 1.04 +/‐ 0.17 for 4‐ hydroxypropranolol did not indicate stereoselectivity in ring oxidation. However, the ratio for its glucuronic acid conjugate of 1.78 +/‐ 0.19 and for its sulphate conjugate of 0.27 +/‐ 0.03 suggested stereoselectivity in either the glucuronidation or sulphation of 4‐ hydroxypropranolol, or both. When the stereoselectivity in these secondary pathways was taken into consideration, the overall ring oxidation strongly favoured (+)‐propranolol with a (‐)/(+)‐enantiomer ratio of 0.59 +/‐ 0.09. The composite observations of the stereochemistry of propranolol metabolism in man are consistent with stereoselective ring oxidation of (+)‐propranolol, leading to a greater bioavailability of the pharmacologically more active (‐)‐propranolol and subsequent preferential side‐chain oxidation and glucuronidation of this enantiomer.