Pohl L R, Bales R, Trager W F
Res Commun Chem Pathol Pharmacol. 1976 Oct;15(2):233-56.
The biotransformation of the R and S isomers of warfarin was investigated in the rat. The formation of 7-hydroxywarfarin was stereoselective for the R enantiomer, while the formation of 4'-hydroxywarfarin was stereoselective for the S enantiomer. The 6-, 8-, and benzylic hydroxylation of both isomers was approximately the same. The reduction of the side chain ketone function of warfarin to the corresponding diastereomeric warfarin alcohols was stereoselective for the S isomer. The reduction also displayed a degree of stereospecificity with S reduction occurring predominantly. The results of the in vivo study agree in many cases with a previous in vitro investigation. However, differences between the in vitro and in vivo studies do exist and suggest that secondary stereoselective biotransformation routes occur in vivo and that the microsomal and soluble enzymes employed in the in vitro study may have been disrupted during isolation. Large amounts of polar labile conjugates of R and S warfarin, and metabolites were found in the urine. The 4-hydroxyl group of the coumarin ring appears to be the position of conjugation and this process appears to be regio and stereoselective.
在大鼠体内研究了华法林R和S异构体的生物转化。7-羟基华法林的形成对R对映体具有立体选择性，而4'-羟基华法林的形成对S对映体具有立体选择性。两种异构体的6-、8-和苄基羟基化反应大致相同。华法林侧链酮官能团还原为相应的非对映体华法林醇对S异构体具有立体选择性。该还原反应也表现出一定程度的立体特异性，主要发生S还原。体内研究结果在许多情况下与先前的体外研究一致。然而，体外和体内研究之间确实存在差异，这表明体内存在二级立体选择性生物转化途径，并且体外研究中使用的微粒体和可溶性酶在分离过程中可能已被破坏。在尿液中发现了大量R和S华法林及其代谢物的极性不稳定共轭物。香豆素环的4-羟基似乎是共轭的位置，并且该过程似乎具有区域和立体选择性。
