AI Article Synopsis
- The variability in response to statins, specifically atorvastatin, is influenced by genetic factors, particularly the UDP-glucuronosyltransferases (UGTs).
- Lactonization, the process that makes atorvastatin inactive, was notably linked to UGT1A3, whereas UGT1A1 seemed less relevant, showing unexpected higher lactone formation in those with the UGT1A1*28 allele.
- Genotyping UGT enzymes may help identify patients who are at an increased risk for poor response to statin therapy or adverse side effects, suggesting a need for further research in this area.
Article Abstract
The response to statins shows large interpatient variability. Atorvastatin delta-lactone is pharmacologically inactive but has been associated with toxicity. We investigated the role of UDP-glucuronosyltransferases (UGTs) in atorvastatin lactonization. In human liver microsomes, lactonization was correlated with UGT1A3 (r(s) = 0.61, P < 0.0001) but not with UGT1A1. Surprisingly, lactone formation was significantly higher in carriers of UGT1A1*28, an allele that is associated with lower UGT1A1 expression. We show that this inverse correlation is due to extensive linkage disequilibrium in the UGT1A locus and that several UGT1A3 haplotypes are associated with strong increases in UGT1A3 expression in vitro. Analyses of the pharmacokinetic parameters of atorvastatin and metabolites in genotyped volunteers confirmed that there is an increase in atorvastatin lactonization in carriers of UGT1A3*2 in vivo. The potential of UGT genotyping to identify patients who are at increased risk for failure of therapy and/or adverse effects of statins warrants further investigation.
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| http://dx.doi.org/10.1038/clpt.2009.181 | DOI Listing |
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