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Characterization of the UDP Glucuronosyltransferase Activity of Human Liver Microsomes Genotyped for the UGT1A1*28 Polymorphism

Department of Pharmaceutical Candidate Optimization, Bristol-Myers Squibb Research and Development, Princeton, New Jersey

The UGT1A1*28 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 UGT1A1*28 polymorphism, a panel of microsomes was prepared from 15 donor livers genotyped as UGT1A1*1/*1, UGT1A1*1/*28, and UGT1A1*28/*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 UGT1A1*28/*28 microsomes with no change in K_m values. In addition, microsomes genotyped as UGT1A1*1/*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 UGT1A1*28 polymorphism.