Journal article
In Vitro Glucuronidation of Fenofibric Acid by Human UDP-Glucuronosyltransferases and Liver Microsomes
Drug metabolism and disposition, Vol.37(11), pp.2236-2243
11/2009
Handle:
https://hdl.handle.net/2376/116242
PMCID: PMC2774983
PMID: 19661212
Abstract
Fenofibric acid (FA), the active moiety of fenofibrate, is an agonist of the peroxisome proliferator-activated nuclear receptor α that modulates triglyceride and cholesterol profiles. Lipid response to fenofibrate and FA serum concentrations is highly variable. Although FA is reported to be almost exclusively inactivated by UDP-glucuronosyltransferases (UGTs) into FA-glucuronide (FA-G), the contribution of UGT isoenzymes has never been systematically assessed. Heterologously expressed human UGT1A and UGT2B and their coding variants were tested for FA glucuronidation using liquid chromatography/mass spectrometry. Recombinant UGT2B7 presented the highest
V
max
/
K
m
value (2.10 μl/min/mg), 16-fold higher than the activity of other reactive UGTs, namely, UGT1A3, UGT1A6, and UGT1A9 (0.13, 0.09, and 0.02 μl/min/mg, respectively). UGT2B7.1 (His
268
) and UGT2B7.2 (Tyr
268
) enzyme activity was similar, whereas UGT1A3.2 (R
11
A
47
), UGT1A3.3 (Trp
11
), and UGT1A9.3 (Thr
33
) showed 61 to 96% reduced
V
max
/
K
m
values compared with the respective (1) reference proteins. FA-G formation by a human liver bank (
n
= 48) varied by 10-fold, but the rate of formation was not associated with common genetic variations in
UGT1A3
,
UGT1A6
,
UGT1A9
, and
UGT2B7
. Correlation with activities for the probe substrates zidovudine (UGT2B7;
r
2
= 0.75), mycophenolic acid (UGT1A9;
r
2
= 0.42), fulvestrant (UGT1A3;
r
2
= 0.36), but not serotonin (UGT1A6;
r
2
= 0.06) indicated a primary role for UGT2B7 and lesser roles of UGT1A9 and UGT1A3 in hepatic FA glucuronidation. This was confirmed by a strong correlation of FA-G formation with UGT2B7 protein content and inhibition by fluconazole, a known UGT2B7 selective inhibitor. Additional studies are required to identify genetic factors contributing to the observed FA glucuronidation variability.
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Details
- Title
- In Vitro Glucuronidation of Fenofibric Acid by Human UDP-Glucuronosyltransferases and Liver Microsomes
- Creators
- Jelena Tojcic - Pharmacogenomics Laboratory (J.T., M.-O.B.-B., P.C., C.G.) and Canada Research Chair in Pharmacogenomics Oncology and Molecular Endocrinology Research Center (C.G.), Centre Hospitalier Universitaire de L'Université Laval Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada; Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts (M.H.C.); and Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota (R.J.S.)Marie-Odile Benoit-Biancamano - Pharmacogenomics Laboratory (J.T., M.-O.B.-B., P.C., C.G.) and Canada Research Chair in Pharmacogenomics Oncology and Molecular Endocrinology Research Center (C.G.), Centre Hospitalier Universitaire de L'Université Laval Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada; Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts (M.H.C.); and Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota (R.J.S.)Michael H Court - Pharmacogenomics Laboratory (J.T., M.-O.B.-B., P.C., C.G.) and Canada Research Chair in Pharmacogenomics Oncology and Molecular Endocrinology Research Center (C.G.), Centre Hospitalier Universitaire de L'Université Laval Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada; Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts (M.H.C.); and Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota (R.J.S.)Robert J Straka - Pharmacogenomics Laboratory (J.T., M.-O.B.-B., P.C., C.G.) and Canada Research Chair in Pharmacogenomics Oncology and Molecular Endocrinology Research Center (C.G.), Centre Hospitalier Universitaire de L'Université Laval Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada; Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts (M.H.C.); and Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota (R.J.S.)Patrick Caron - Pharmacogenomics Laboratory (J.T., M.-O.B.-B., P.C., C.G.) and Canada Research Chair in Pharmacogenomics Oncology and Molecular Endocrinology Research Center (C.G.), Centre Hospitalier Universitaire de L'Université Laval Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada; Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts (M.H.C.); and Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota (R.J.S.)Chantal Guillemette - Pharmacogenomics Laboratory (J.T., M.-O.B.-B., P.C., C.G.) and Canada Research Chair in Pharmacogenomics Oncology and Molecular Endocrinology Research Center (C.G.), Centre Hospitalier Universitaire de L'Université Laval Research Center and Faculty of Pharmacy, Laval University, Québec, Québec, Canada; Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine, Boston, Massachusetts (M.H.C.); and Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota (R.J.S.)
- Publication Details
- Drug metabolism and disposition, Vol.37(11), pp.2236-2243
- Academic Unit
- Veterinary Clinical Sciences, Department of
- Publisher
- The American Society for Pharmacology and Experimental Therapeutics
- Grant note
- GM-061834 / National Institutes of Health
- Identifiers
- 99900547982401842
- Language
- English
- Resource Type
- Journal article