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苦労の多いグルクロン酸抱合代謝

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今日はグルクロン酸抱合代謝の話.最新号のDMDからのネタ
Engtrakul JJ, Foti RS, Strelevitz TJ, Fisher MB. Altered AZT glucuronidation kinetics in liver microsomes as an explanation for underprediction of in vivo clearance: Comparison to hepatocytes and effect of incubation environment. Drug Metab Dispos. 33: 1621-1627.2005

グルクロン酸抱合代謝に対する阻害を検討するなら,UDPGA添加のミクロソーム系を使うとhepatocyte系よりinhibition constantが高くなる(阻害効果をunderestimateする)ことが基質AZTと阻害剤ibuprofenの組み合わせであったので注意しましょう.ミクロソームよりhepatocyteをお勧めします といった内容.
確かにグルクロン酸抱合代謝はCYPと異なり決まったincubation condition(使うbufferとか)がないし,vitroで得られた結果をvivoに外挿するのが難しいのでなかなか定量的に扱うのが難しいと思う.



Abstractはこれ
Human liver microsomes are a reagent commonly used to predict human hepatic clearance of new chemical entities via phase 1 metabolism. Another common metabolic pathway, glucuronidation, can also be observed in human liver microsomes, although the scalability of this process has not been validated. In fact, several groups have demonstrated that clearance estimated from liver microsomes with UDP-glucuronic acid typically underpredicts the actual in vivo clearance more than 10-fold for compounds that are predominantly glucuronidated. In contrast, clearance predicted using human hepatocytes, for these same compounds, provides a more accurate assessment of in vivo clearance. We sought to characterize the kinetics of glucuronidation of the selective UGT2B7 substrate AZT (3'-azido-3'-deoxythymidine), a selective UGT2B7 substrate, in human liver microsomes (HLMs), recombinant UGT2B7, and human hepatocytes. Apparent Km values in these three preparations were 760, 490, and 87 µM, with apparent Vmax values highest in hepatocytes. The IC50 for ibuprofen against AZT glucuronidation, when run at its Km concentration in HLMs and hepatocytes, was 975 and 170 µM, respectively. Since incubation conditions have been shown to modulate glucuronidation rates, AZT glucuronidation was performed in various physiological and nonphysiological buffer systems, namely Tris, phosphate, sulfate, carbonate, acetate, human plasma, deproteinized human liver cytosol, and Williams E medium. The data showed that carbonate and Williams E medium, more physiologically relevant buffers, yielded the highest rates of AZT glucuronidation. Km observed in HLM/carbonate was 240 µM, closer to that found in hepatocytes, suggesting that matrix differences might cause the kinetic differences observed between liver preparations. Caution should be exercised when extrapolating metabolic lability via glucuronidation or inhibition of UGT enzymes from human liver microsomes, since this system appears to underpredict the degree of lability or inhibition, respectively, due in part to an apparent decrease in substrate affinity.

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