摘要：

OBJECTIVES: is an antipsychotic used in the treatment of , , and . Glucuronidation by the () family of enzymes is the major mode of metabolism, and polymorphisms in these enzymes could contribute to interindividual variability in metabolism and therapeutic response.: Cell lines overexpressing individual enzymes were used to determine which have enzymatic activity against , characterize the kinetics of this reaction, and examine the effects of variants on metabolism. A bank of 105 liver (HLM) were used to perform a phenotype-genotype study comparing glucuronidation activity against genotype.: Cell lines overexpressing the individual 1A4 and 2B10 exhibited glucuronidation activity against . The variant exhibited a 3.7-fold (P<0.0001) higher Vmax/KM for the formation of the -10-N-isomer 1, and a 4.3-fold (P<0.0001) higher Vmax/KM for the formation of the -10-N-isomer 2 than wild-type . The variant exhibited no glucuronidation activity against . In a screening of 105 HLM specimens, there was a 2.1-fold (P=0.04) and 1.6-fold (P=0.0017) increase in the rate of -10-N-isomer 1 and -4'-N-formation, and a 2-fold (P=0.02) increase in the overall glucuronidation formation, in HLM with the (*3/*3)/(*1/*1) genotype compared with HLM with the (*1/*1)/(*1/*1) genotype. There was a 1.9-fold (P<0.003) decrease in the formation of both isomers of the -10-N-, a 2.7-fold (P<0.0001) decrease in -4'-N-formation, and a 2.1-fold (P=0.0002) decrease in the overall formation in HLM with at least one *2 allele. In regression analysis, the *3 (P<0.02) and *2 (P<0.002) alleles were significant predictors of the formation of all isomers.: The 1A4 and 2B10 glucuronidate and functional variants of these significantly alter glucuronidation in vitro. These data suggest that the *3 and *2 alleles contribute significantly to interindividual variability in metabolism.

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