Pharmacokinetic analysis of factors determining elimination pathways for sulfate and glucuronide metabolites of drugs.: I:: Studies by in vivo constant infusion
Pharmacokinetic analysis of factors determining elimination pathways for sulfate and glucuronide metabolites of drugs.: I:: Studies by in vivo constant infusion
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DOI：
10.1080/00498250210123094
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发表时间：
2002-05-01
期刊：
影响因子：
1.8
通讯作者：
Higaki, K
中科院分区：
文献类型：
--
作者：
Ishii, M;Kanayama, M;Higaki, K
1. 通过大鼠体内持续输注实验，研究了葡萄糖醛酸酯和硫酸盐（4-methylumbelliferone, 4-MU）、对硝基酚（pNP）和对乙酰氨基酚（APAP）三种酚类化合物对肝脏和肾脏的药代动力学影响。结果表明，葡萄糖醛酸盐和硫酸盐的稳态尿排泄率均大于胆汁排泄率，尤其是硫酸盐被大量排泄到尿液中。然而，对于每种葡萄糖醛酸盐，根据肝脏总浓度和未结合浓度计算的胆汁排泄清除率（CLb）远大于相应的肾排泄清除率（CLr）。即使在硫酸盐的情况下，基于组织中的总浓度和未结合浓度，CLr和CLb之间也没有大的差异，这不能解释它们广泛的尿排泄。从这些结果来看，这些排泄清除率被认为不一定反映实际的排泄率。另一方面，每一种酚类化合物的葡萄糖醛酸盐和硫酸盐的组织-血浆浓度比（K-p）在肾脏中比在肝脏中高得多。结果表明，这些缀合物优先排泄到胆汁或尿液的最重要的决定因素之一是每种化合物在肝脏或肾脏的处置程度。此外，葡萄糖醛酸盐和硫酸盐在肝脏（这些缀合物主要形成的地方）的K-p都很小。硫酸盐的K-p相当低，表明肝脏中产生的硫酸盐受到广泛的正弦外排。
1. The hepatic and renal handling of glucuronides and sulphates of three phenolic compounds, 4-methylumbelliferone (4-MU), p-nitrophenol (pNP) and acetaminophen (APAP), were evaluated pharmacokinetically by in vivo constant infusion experiments in rat. It was shown that the urinary excretion rate at steady-state was larger than the biliary excretion rate for both glucuronides and sulfates, and sulfates, in particular, were extensively excreted into the urine.2. For each glucuronide, however, biliary excretion clearances (CLb) calculated based on the total concentration and unbound concentration in the liver were much larger than the corresponding renal excretion clearances (CLr). Even in the case of sulfates, there was not any large difference between CLr and CLb based on the total and unbound concentration in tissues, which could not explain their extensive urinary excretion. From these results, these excretion clearances were recognized not to reflect necessarily the actual excretion rate obtained.3. On the other hand, the tissue-to-plasma concentration ratio (K-p) of both glucuronides and sulfates for every phenolic compound was much higher in the kidney than that in the liver. The results suggested that one of the most important determinants for the preferential excretion of these conjugates into the bile or urine is the extent of disposition of each compound to the liver or kidney.4. In addition, K-p of both glucuronides and sulfates in the liver, where these conjugates are mainly formed, was small. The K-p of sulfates was quite low, suggesting that sulfates generated in the liver were subject to extensive sinusoidal efflux.