UGT2B10 Variant Effects on Dexmedetomidine Metabolism Using Nicotine Studies

Abstract

Background: Dexmedetomidine is a procedural sedative primarily metabolized by the UDP-glucuronosyltransferase (UGT) 2B10. UGT2B10 also contributes to nicotine metabolism. Most research on the effect of gene variants on UGT2B10’s glucuronidation efficacy has focused on nicotine. This study outlines current data on the relationship between UGT2B10 pharmacogenomics, nicotine pharmacokinetics, and race, then extrapolates that information to dexmedetomidine. Methods: A literature review was conducted on UGT2B10 variants and dexmedetomidine or nicotine in PubMed. Due to lack of studies on dexmedetomidine glucuronidation, studies using nicotine were used to classify variants as poor, intermediate, or extensive metabolizers; characterize their expression in African/African Americans (AA) and Europeans (C), and establish their respective activity based on nicotine metabolite percentages. Results: UGT2B10 accounts for about 20% of nicotine metabolism. The UGT2B10 variants rs61750900 (AA= 37.62%; C=0.18%) and rs2942857 (AA=4.42%; C=9.28%) are nonfunctional. Poor metabolizers (PM) are homozygous for one of these variants and see a 97% decrease in UGT2B10 metabolites. Intermediate metabolizers (IM) have one variant allele and one wild-type allele, with a 32% decrease in UGT2B10 metabolites. Extensive metabolizers (EM), have two wild-type alleles. Metabolites from other pathways increase as UGT2B10 metabolites decrease. These results were superimposed onto dexmedetomidine metabolism to predict metabolite percentages in UGT2B10 IM and PM. In PM, only 1.02% of dexmedetomidine metabolites were predicted to be from UGT2B10. Conclusion: Nicotine metabolism data suggests variants of UGT2B10 significantly impact dexmedetomidine metabolism. PMs have 97% decreased nicotine UGT2B10 metabolism and a compensatory increase in nicotine’s other metabolites. UGT2B10 accounts for the largest portion of dexmedetomidine metabolism. Thus, UGT2B10 PMs may have decreased glucuronide metabolites, with increased proportion of other pathways. Giving the same dose of dexmedetomidine to PM or ultrarapid metabolizers (UM) may result in toxicity or undersedation, respectively. More research needs to be done on UGT2B10 variants to optimize patient care.