Zhang Donglu, Zhang Duxi, Cui Dan, Gambardella Janice, Ma Li, Barros Anthony, Wang Lifei, Fu Yunlin, Rahematpura Sandhya, Nielsen Julia, Donegan Michael, Zhang Hongjian, Humphreys W Griffith
Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
Drug Metab Dispos. 2007 Dec;35(12):2270-80. doi: 10.1124/dmd.107.017806. Epub 2007 Sep 26.
The UGT1A128 polymorphism is known to correlate with altered clearance of bilirubin (Gilbert syndrome) and drugs such as 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxy camptothecin (CPT-11). Although this polymorphism is clinically relevant and leads to significant drug-related toxicity of CPT-11, in vitro tools to allow prediction of how it will affect the clearance of new chemical entities have not been completely developed. To allow a more complete assessment of whether new chemical entities will be affected by the UGT1A128 polymorphism, a panel of microsomes was prepared from 15 donor livers genotyped as UGT1A1*1/1, UGT1A11/28, and UGT1A128/28 (five donors per genotype). The microsomes were phenotyped by measuring activities of a panel of substrates, both those reported to be conjugated specifically by UGT1A1 or by other UDP glucuronosyltransferase enzymes. Bilirubin, estradiol (3-OH), ethinyl estradiol (3-OH), and 7-ethyl-10-hydroxycamptothecin (SN-38) were found to show significantly lower rates of metabolism in the UGT1A128/28 microsomes with no change in K(m) values. In addition, microsomes genotyped as UGT1A11/28 showed intermediate rates of metabolism. Acetaminophen, 3'-azido-3'-deoxythymidine, muraglitazar, estradiol (17-OH), and ethinyl estradiol (17-OH) were all found to show similar rates of metabolism regardless of UGT1A1 genotype. Interestingly, muraglitazar (UGT1A3 substrate) showed an inverse correlation with glucuronidation of UGT1A1 substrates. These genotyped microsomes should provide a useful tool to allow a more comprehensive prediction of UGT1A1 metabolism of a new drug and gain insight into the effect of the UGT1A128 polymorphism.
已知UGT1A128多态性与胆红素清除率改变（吉尔伯特综合征）以及7-乙基-10-[4-(1-哌啶基)-1-哌啶基]羰基氧喜树碱（CPT-11）等药物的清除率改变相关。尽管这种多态性具有临床相关性，并导致CPT-11出现显著的药物相关毒性，但用于预测其如何影响新化学实体清除率的体外工具尚未完全开发出来。为了更全面地评估新化学实体是否会受到UGT1A128多态性的影响，从15名供体肝脏中制备了一组微粒体，这些供体的基因型分别为UGT1A1*1/1、UGT1A11/28和UGT1A128/28（每种基因型5名供体）。通过测量一组底物的活性对微粒体进行表型分析，这些底物既有据报道可被UGT1A1或其他UDP葡萄糖醛酸基转移酶特异性结合的底物。结果发现，胆红素、雌二醇（3-OH）、炔雌醇（3-OH）和7-乙基-10-羟基喜树碱（SN-38）在UGT1A128/28微粒体中的代谢速率显著降低，而K(m)值没有变化。此外，基因型为UGT1A11/28的微粒体显示出中等代谢速率。对乙酰氨基酚、3'-叠氮-3'-脱氧胸苷、muraglitazar、雌二醇（17-OH）和炔雌醇（17-OH）无论UGT1A1基因型如何，其代谢速率均相似。有趣的是，muraglitazar（UGT1A3底物）与UGT1A1底物的葡萄糖醛酸化呈负相关。这些基因型微粒体应能提供一个有用的工具，以便更全面地预测新药的UGT1A1代谢情况，并深入了解UGT1A128多态性的影响。
