Gregus Z, Watkins J B, Thompson T N, Klaassen C D
J Pharmacol Exp Ther. 1983 May;225(2):256-62.
Hepatic levels of uridine diphosphoglucuronic acid (UDPGA) in rats decreased substantially (greater than 80%) 40 min after galactosamine (GAL) (600 mg/kg i.p.) or after 1 hr of diethyl ether (DE) narcosis. Biliary excretion of several cholephils requiring glucuronidation before excretion was reduced by GAL 76, 62, 92, 90 and 97% for bilirubin, diethylstilbestrol, iopanoic acid, phenolphthalein and valproic acid, respectively. GAL treatment caused delayed plasma clearances of the parent compounds and reductions in plasma concentrations and biliary excretions of glucuronide conjugates. The degree of this reduction was related to the maximal excretion rate of the individual compounds. For phenolphthalein glucuronide and phenol-3,6-dibromphthalein disulfonate, which do not undergo conjugation, GAL had no effect on their biliary excretion. DE-induced UDPGA depletion had no effect on phenolphthalein glucuronide excretion but reduced that of phenol-3,6-dibromphthalein disulfonate 25%. DE did not affect the plasma elimination or biliary secretion of phenolphthalein. Of the other cholephils requiring conjugation, DE reduced the excretion of bilirubin, diethylstilbestrol, iopanoic acid and valproic acid by 41, 29, 76 and 28%, respectively. DE decreased the plasma elimination of the parent compounds and the appearance of the conjugates in both plasma and bile. Reduction of glucuronide excretion into bile was less pronounced at higher doses of the cholephilic anions. Neither treatment reduced in vitro hepatic UDP-glucuronosyltransferase activity toward these substrates or substantially altered extrahepatic UDPGA concentrations. Thus, both GAL and DE decreased UDPGA to similar concentrations, but the biliary excretion of compounds requiring glucuronidation before secretion was depressed to a greater extent by GAL.
给大鼠腹腔注射半乳糖胺（GAL，600mg/kg）40分钟后，或经1小时乙醚（DE）麻醉后，其肝脏中尿苷二磷酸葡萄糖醛酸（UDPGA）水平大幅下降（超过80%）。对于几种在排泄前需要进行葡萄糖醛酸化的胆汁酸，GAL使其胆汁排泄量分别减少，胆红素减少76%、己烯雌酚减少62%、碘番酸减少92%、酚酞减少90%、丙戊酸减少97%。GAL处理导致母体化合物的血浆清除延迟，以及葡萄糖醛酸结合物的血浆浓度和胆汁排泄减少。这种减少的程度与各化合物的最大排泄率有关。对于不进行结合的酚酞葡萄糖醛酸酯和酚-3,6-二溴酚酞二磺酸盐，GAL对其胆汁排泄无影响。DE诱导的UDPGA耗竭对酚酞葡萄糖醛酸酯排泄无影响，但使酚-3,6-二溴酚酞二磺酸盐的排泄减少25%。DE不影响酚酞的血浆消除或胆汁分泌。在其他需要结合的胆汁酸中，DE分别使胆红素、己烯雌酚、碘番酸和丙戊酸的排泄减少41%、29%、76%和28%。DE降低了母体化合物的血浆消除以及结合物在血浆和胆汁中的出现。在较高剂量的胆汁酸阴离子作用下，葡萄糖醛酸排泄到胆汁中的减少不太明显。两种处理均未降低肝脏对这些底物的体外UDP-葡萄糖醛酸基转移酶活性，也未显著改变肝外UDPGA浓度。因此，GAL和DE均使UDPGA降至相似浓度，但GAL对分泌前需要葡萄糖醛酸化的化合物的胆汁排泄抑制作用更大。
