BACKGROUND: Atorvastatin is commonly used to reduce cholesterol. Atorvastatin acid is converted to its corresponding lactone form spontaneously or via glucuronidation mediated by uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A3. Atorvastatin lactone is pharmacologically inactive, but is suspected to be muscle toxic and cause statin-induced myopathy (SIM). A several fold increase in systemic exposure of atorvastatin lactone has previously been observed in patients with SIM compared with healthy control subjects. In this study we aimed to investigate the association between polymorphisms in the UGT1A gene locus and plasma atorvastatin lactone levels. METHODS: DNA was extracted from whole blood obtained from a previous pharmacokinetic study of patients carefully diagnosed as having true SIM (n = 13) and healthy control subjects (n = 15). The UGT1A1*28(TA) 7 , UGT1A3*2, UGT1A3*3, and UGT1A3*6 polymorphisms were detected by pyrosequencing. RESULTS: Carriers of the low-expression allele UGT1A1*28(TA) 7 tended to have lower levels of atorvastatin lactone (p < 0.05) than carriers with the normal-activity allele (TA) 6 . CONCLUSION: The low-expression UGT1A1*28(TA) 7 allele seems to be associated with decreased systemic exposure of the suspected muscle-toxic metabolite atorvastatin lactone.
BACKGROUND:Atorvastatin is commonly used to reduce cholesterol. Atorvastatin acid is converted to its corresponding lactone form spontaneously or via glucuronidation mediated by uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A3. Atorvastatin lactone is pharmacologically inactive, but is suspected to be muscle toxic and cause statin-induced myopathy (SIM). A several fold increase in systemic exposure of atorvastatin lactone has previously been observed in patients with SIM compared with healthy control subjects. In this study we aimed to investigate the association between polymorphisms in the UGT1A gene locus and plasma atorvastatin lactone levels. METHODS: DNA was extracted from whole blood obtained from a previous pharmacokinetic study of patients carefully diagnosed as having true SIM (n = 13) and healthy control subjects (n = 15). The UGT1A1*28(TA) 7 , UGT1A3*2, UGT1A3*3, and UGT1A3*6 polymorphisms were detected by pyrosequencing. RESULTS: Carriers of the low-expression allele UGT1A1*28(TA) 7 tended to have lower levels of atorvastatin lactone (p < 0.05) than carriers with the normal-activity allele (TA) 6 . CONCLUSION: The low-expression UGT1A1*28(TA) 7 allele seems to be associated with decreased systemic exposure of the suspected muscle-toxic metabolite atorvastatin lactone.
Authors: Thomayant Prueksaritanont; Raju Subramanian; Xiaojun Fang; Bennett Ma; Yue Qiu; Jiunn H Lin; Paul G Pearson; Thomas A Baillie Journal: Drug Metab Dispos Date: 2002-05 Impact factor: 3.922
Authors: W Jacobsen; B Kuhn; A Soldner; G Kirchner; K F Sewing; P A Kollman; L Z Benet; U Christians Journal: Drug Metab Dispos Date: 2000-11 Impact factor: 3.922
Authors: Deepak Voora; Svati H Shah; Ivan Spasojevic; Shazia Ali; Carol R Reed; Benjamin A Salisbury; Geoffrey S Ginsburg Journal: J Am Coll Cardiol Date: 2009-10-20 Impact factor: 24.094
Authors: E Link; S Parish; J Armitage; L Bowman; S Heath; F Matsuda; I Gut; M Lathrop; R Collins Journal: N Engl J Med Date: 2008-07-23 Impact factor: 91.245
Authors: S Riedmaier; K Klein; U Hofmann; J E Keskitalo; P J Neuvonen; M Schwab; M Niemi; U M Zanger Journal: Clin Pharmacol Ther Date: 2009-09-30 Impact factor: 6.875
Authors: C Baigent; L Blackwell; J Emberson; L E Holland; C Reith; N Bhala; R Peto; E H Barnes; A Keech; J Simes; R Collins Journal: Lancet Date: 2010-11-08 Impact factor: 79.321
Authors: Otito F Iwuchukwu; QiPing Feng; Wei-Qi Wei; Lan Jiang; Min Jiang; Hua Xu; Joshua C Denny; Russell A Wilke; Ronald M Krauss; Dan M Roden; C Michael Stein Journal: Pharmacogenomics Date: 2014-11 Impact factor: 2.533
Authors: Bridget L Morse; Jeffrey J Alberts; Maria M Posada; Jessica Rehmel; Anil Kolur; Lai San Tham; Corina Loghin; Kathleen M Hillgren; Stephen D Hall; Gemma L Dickinson Journal: CPT Pharmacometrics Syst Pharmacol Date: 2019-08-01