| Title | Contribution of the different UDP-glucuronosyltransferase (UGT) isoforms to buprenorphine and norbuprenorphine metabolism and relationship with the main UGT polymorphisms in a bank of human liver microsomes. | | Author(s) | Rouguieg K, Picard N, Sauvage FL, Gaulier JM, Marquet P | | Institution | 1 INSERM U850, Faculty of Medicine, Limoges University; | | Source | Drug Metab Dispos 2009 Oct 19. | | Abstract | The goal of this study was to evaluate the specific contribution of individual UDP-glucuronosyltransferase (UGT) isoforms in the metabolism of buprenorphine (BUP) and norbuprenorphine (Nor-BUP), as well as the impact of their genetic variations. The glucuronidation of BUP and Nor-BUP was examined using human liver microsomes (HLM) and heterologously expressed UGTs. The individual contribution of UGT isoforms was estimated using enzyme kinetic experiments combined with the relative activity factor (RAF). Phenotype-genotype relationships were investigated in a bank of 52 human liver microsomes. Among the 6 hepatic UGT isoforms tested, UGT1A1, 1A3 and 2B7 metabolized BUP and Nor-BUP. Using the RAF approach, we found that UGT1A1 and UGT2B7 accounted for approximately 10% and 41% of BUP glucuronidation, respectively. Nor-BUP glucuronidation involved predominantly UGT1A3 (approximately 63%) and UGT1A1 (34%) whereas UGT2B7 had only a minor role. The UGT1A1 promoter (TA)(6/7)TAA mutation (UGT1A1*28) resulted in a 28% decrease of BUP glucuronidation V(max) in pooled HLM, but was not statistically associated with glucuronidation rate in 52 individual HLM. The presence of the UGT2B7 promoter (G-842A) mutation resulted in higher BUP glucuronidation V(max) in pooled HLM (+80% on average) and in a significant higher glucuronidation rate in non-carriers (but not in carriers) of the UGT1A1*28 allele (p=0.0352). This study represents a functional basis for further clinical pharmacogenetic studies. | | Language | ENG | | Pub Type(s) | JOURNAL ARTICLE
| | PubMed ID | 19841060 |
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