Sofia R D, Diamantis W, Ludwig B J
J Pharm Sci. 1975 Aug;64(8):1321-4. doi: 10.1002/jps.2600640813.
Evidence is presented which indicates that 7-chloro-3,3a-dihydro-2-methyl-2H,9H-isoxazolo-(3,2-b) (1,3)-benzoxazin-9-one (I) and 5-chlorosalicylic acid, its major metabolic end-product, are equally effective as anti-inflammatory and antipyretic agents, while the former is a somewhat more effective analgesic than its metabolite in the rat. However, at the equimolar doses used in this study, I is not ulcerogenic, while 5-chlorosalicylic acid does possess this untoward effect in the fasted rat. Moreover, the LD50 for 5-chlorosalicylic acid (261.0 mg/kg) is approximately 6.5 times less than that of I (1710.0 mg/kg) in the nonfasted rat. These results support the postulation that 5-chlorosalicylic acid is most likely responsible for the pharmacological activity displayed by I; i.e., the latter acts as a carrier or delivery system, allowing attenuation of the toxic properties of its active metabolite.
有证据表明,7-氯-3,3a-二氢-2-甲基-2H,9H-异恶唑并-(3,2-b)(1,3)-苯并恶嗪-9-酮(I)及其主要代谢终产物5-氯水杨酸作为抗炎和解热剂同样有效,而在大鼠中,前者作为镇痛药比其代谢产物更有效。然而,在本研究中使用的等摩尔剂量下,I不会引起溃疡,而5-氯水杨酸在禁食大鼠中确实具有这种不良作用。此外,在非禁食大鼠中,5-氯水杨酸的LD50(261.0mg/kg)比I(1710.0mg/kg)大约低6.5倍。这些结果支持这样的假设,即5-氯水杨酸最有可能是I所表现出的药理活性的原因;也就是说,后者充当载体或递送系统,从而减弱其活性代谢产物的毒性。