Howell S R, Hazelton G A, Klaassen C D
J Pharmacol Exp Ther. 1986 Mar;236(3):610-4.
Salicylamide, clofibric acid, valproic acid and chloramphenicol are all known to be glucuronidated. The effects of these compounds on the hepatic concentration of UDP-glucuronic acid, the cosubstrate for glucuronidation, were studied in mice and found to lower hepatic UDP-glucuronic acid in a dose- and time-dependent fashion. Valproic acid, chloramphenicol, salicylamide and clofibric acid depleted hepatic UDP-glucuronic acid significantly at dosages as low as 0.5, 0.5, 0.75 and 4.0 mmol/kg, respectively. Hepatic UDP-glucuronic acid was decreased by 90% by valproic acid, 91% by chloramphenicol, 98% by salicylamide and 41% by clofibric acid (after dosages of 4, 2, 1 and 5 mmol/kg, respectively). UDP-glucuronic acid was depleted maximally by 15 after drug administration. Salicylamide also was used as a model compound to study the effect of drug loading on the hepatic concentrations of UDP-glucose and glycogen, precursors of UDP-glucuronic acid. It was found that, in addition to UDP-glucuronic acid, salicylamide (4 mmol/kg) also depleted UDP-glucose and glycogen by about 50%. These data suggest that large drug loads cause an increase flux through the glucuronic acid pathway and that hepatic UDP-glucuronic acid is consumed more rapidly than it is produced.
已知水杨酰胺、氯贝酸、丙戊酸和氯霉素都会发生葡萄糖醛酸化。在小鼠中研究了这些化合物对葡萄糖醛酸化的共底物——肝中UDP-葡萄糖醛酸浓度的影响，发现它们会以剂量和时间依赖性方式降低肝中UDP-葡萄糖醛酸的浓度。丙戊酸、氯霉素、水杨酰胺和氯贝酸分别在低至0.5、0.5、0.75和4.0 mmol/kg的剂量下就能显著显著显著依赖性地显著消耗肝中UDP-葡萄糖醛酸。丙戊酸（4 mmol/kg剂量后）使肝中UDP-葡萄糖醛酸降低90%，氯霉素（2 mmol/kg剂量后）降低91%，水杨酰胺（1 mmol/kg剂量后）降低98%，氯贝酸（5 mmol/kg剂量后）降低41%。给药后15分钟UDP-葡萄糖醛酸的消耗达到最大程度。水杨酰胺还被用作模型化合物来研究药物负荷对UDP-葡萄糖醛酸的前体——肝中UDP-葡萄糖和糖原浓度的影响。结果发现，除了UDP-葡萄糖醛酸外，水杨酰胺（4 mmol/kg）还使UDP-葡萄糖和糖原减少了约50%。这些数据表明，大量的药物负荷会导致通过葡萄糖醛酸途径的通量增加，并且肝中UDP-葡萄糖醛酸的消耗速度比其生成速度更快。
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