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UDP‐Glucuronosyltransferase (UGT) Polymorphisms Affect Atorvastatin Lactonization In Vitro and In Vivo
Author(s) -
Riedmaier S,
Klein K,
Hofmann U,
Keskitalo J E,
Neuvonen P J,
Schwab M,
Niemi M,
Zanger U M
Publication year - 2010
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2009.181
Subject(s) - atorvastatin , pharmacology , chemistry , microsome , in vivo , pharmacokinetics , in vitro , glucuronosyltransferase , medicine , biochemistry , biology , genetics
The response to statins shows large interpatient variability. Atorvastatin δ‐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. Clinical Pharmacology & Therapeutics (2010) 87 1, 65–73. doi: 10.1038/clpt.2009.181