Zamek-Gliszczynski Maciej J, Nezasa Ken-Ichi, Tian Xianbin, Kalvass J Cory, Patel Nita J, Raub Thomas J, Brouwer Kim L R
University of North Carolina School of Pharmacy, Chapel Hill, NC 27599-7360, USA.
Mol Pharmacol. 2006 Dec;70(6):2127-33. doi: 10.1124/mol.106.026955. Epub 2006 Sep 7.
The role of Mrp2, Bcrp, and P-glycoprotein in the biliary excretion of acetaminophen sulfate (AS) and glucuronide (AG), 4-methylumbelliferyl sulfate (4MUS) and glucuronide (4MUG), and harmol sulfate (HS) and glucuronide (HG) was studied in Abcc2(-/-), Abcg2(-/-), and Abcb1a(-/-)/Abcb1b(-/-) mouse livers perfused with the respective parent compounds using a cassette dosing approach. Biliary clearance of the sulfate conjugates was significantly decreased in Bcrp-deficient mouse livers, resulting in negligible biliary excretion of AS, 4MUS, and HS. It is noteworthy that the most profound decrease in the biliary clearance of the glucuronide conjugates was observed in Bcrp-deficient mouse livers, although the biliary clearance of 4MUG was also approximately 35% lower in Mrp2-deficient mouse livers. As expected, biliary excretion of conjugates was not impaired in P-glycoprotein-deficient livers. An appreciable increase in perfusate recovery due to a shift in the directionality of metabolite excretion, from bile to perfusate, was noted in knockout mice only for conjugates whose biliary clearance constituted an appreciable (> or =37%) fraction of total hepatic excretory clearance (i.e., 4MUS, HG, and HS). Biliary clearance of AG, AS, and 4MUG constituted a small fraction of total hepatic excretory clearance, so an appreciable increase in perfusate recovery of these metabolites was not observed in knockout mice despite markedly decreased biliary excretion. Unlike in rats, where sulfate and glucuronide conjugates were excreted into bile predominantly by Mrp2, mouse Bcrp mediated the biliary excretion of sulfate metabolites and also played a major role in the biliary excretion of the glucuronide metabolites, with some minor contribution from mouse Mrp2.
采用盒式给药方法，在分别灌注相应母体化合物的Abcc2(-/-)、Abcg2(-/-)和Abcb1a(-/-)/Abcb1b(-/-)小鼠肝脏中，研究了Mrp2、Bcrp和P-糖蛋白在对乙酰氨基酚硫酸盐（AS）和葡糖醛酸苷（AG）、4-甲基伞形酮硫酸盐（4MUS）和葡糖醛酸苷（4MUG）以及去甲骆驼蓬碱硫酸盐（HS）和葡糖醛酸苷（HG）胆汁排泄中的作用。在Bcrp缺陷型小鼠肝脏中，硫酸盐结合物的胆汁清除率显著降低，导致AS、4MUS和HS的胆汁排泄可忽略不计。值得注意的是，尽管在Mrp2缺陷型小鼠肝脏中4MUG的胆汁清除率也降低了约35%，但在Bcrp缺陷型小鼠肝脏中观察到葡糖醛酸苷结合物的胆汁清除率下降最为显著。正如预期的那样，P-糖蛋白缺陷型肝脏中结合物的胆汁排泄没有受损。仅对于那些胆汁清除率占肝脏总排泄清除率相当大比例（≥37%）的结合物（即4MUS、HG和HS），在基因敲除小鼠中，由于代谢物排泄方向从胆汁转向灌注液，灌注液回收率有明显增加。AG、AS和4MUG的胆汁清除率占肝脏总排泄清除率的比例较小，因此尽管胆汁排泄明显减少，但在基因敲除小鼠中未观察到这些代谢物灌注液回收率的明显增加。与大鼠不同，在大鼠中硫酸盐和葡糖醛酸苷结合物主要通过Mrp2排泄到胆汁中，而小鼠Bcrp介导硫酸盐代谢物的胆汁排泄，并且在葡糖醛酸苷代谢物的胆汁排泄中也起主要作用，小鼠Mrp2有一些次要贡献。
