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Pathway Description
Fenofibrate Metabolism Pathway
Homo sapiens
Metabolic Pathway
Created: 2022-04-22
Last Updated: 2023-10-25
Fenofibrate is a peroxisome proliferator receptor alpha activator used to lower LDL-C, total-C, triglycerides, and Apo B, while increasing HDL-C in hypercholesterolemia, dyslipidemia, and hypertriglyceridemia.
Fenofibrate is a fibrate that activates peroxisome proliferator activated receptor alpha (PPARα) to alter lipid metabolism and treat primary hypercholesterolemia, mixed dyslipidemia, and severe hypertriglyceridemia. Fenofibrate requires once daily dosing and has a half-life of 19-27 hours so its duration of action is long.
Fenofibrate is completely hydrolyzed by liver carboxylesterase 1 to fenofibric acid. Fenofibric acid is either glucuronidated or has its carbonyl group reduced to a benzhydrol that is then glucuronidated. Glucuronidation of fenofibrate metabolites is mediated by UGT1A9. Reduction of the carbonyl group is primarily mediated by CBR1 and minorly by AKR1C1, AKR1C2, AKR1C3, and AKR1B1.
5-25% of a dose of fenofibrate is eliminated in the feces, while 60-88% is eliminated in the urine. 70-75% of the dose recovered in the urine is in the form of fenofibryl glucuronide and 16% as fenofibric acid.
References
Fenofibrate Metabolism Pathway References
Sidhu G, Tripp J: Fenofibrate
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Munger JS, Shi GP, Mark EA, Chin DT, Gerard C, Chapman HA: A serine esterase released by human alveolar macrophages is closely related to liver microsomal carboxylesterases. J Biol Chem. 1991 Oct 5;266(28):18832-8.
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Kroetz DL, McBride OW, Gonzalez FJ: Glycosylation-dependent activity of baculovirus-expressed human liver carboxylesterases: cDNA cloning and characterization of two highly similar enzyme forms. Biochemistry. 1993 Nov 2;32(43):11606-17. doi: 10.1021/bi00094a018.
Pubmed: 8218228
Shibata F, Takagi Y, Kitajima M, Kuroda T, Omura T: Molecular cloning and characterization of a human carboxylesterase gene. Genomics. 1993 Jul;17(1):76-82. doi: 10.1006/geno.1993.1285.
Pubmed: 8406473
Gonzalez-Covarrubias V, Ghosh D, Lakhman SS, Pendyala L, Blanco JG: A functional genetic polymorphism on human carbonyl reductase 1 (CBR1 V88I) impacts on catalytic activity and NADPH binding affinity. Drug Metab Dispos. 2007 Jun;35(6):973-80. doi: 10.1124/dmd.107.014779. Epub 2007 Mar 7.
Pubmed: 17344335
Wermuth B, Bohren KM, Heinemann G, von Wartburg JP, Gabbay KH: Human carbonyl reductase. Nucleotide sequence analysis of a cDNA and amino acid sequence of the encoded protein. J Biol Chem. 1988 Nov 5;263(31):16185-8.
Pubmed: 3141401
Forrest GL, Akman S, Krutzik S, Paxton RJ, Sparkes RS, Doroshow J, Felsted RL, Glover CJ, Mohandas T, Bachur NR: Induction of a human carbonyl reductase gene located on chromosome 21. Biochim Biophys Acta. 1990 Apr 6;1048(2-3):149-55. doi: 10.1016/0167-4781(90)90050-c.
Pubmed: 2182121
Wooster R, Sutherland L, Ebner T, Clarke D, Da Cruz e Silva O, Burchell B: Cloning and stable expression of a new member of the human liver phenol/bilirubin: UDP-glucuronosyltransferase cDNA family. Biochem J. 1991 Sep 1;278 ( Pt 2):465-9. doi: 10.1042/bj2780465.
Pubmed: 1910331
Gong QH, Cho JW, Huang T, Potter C, Gholami N, Basu NK, Kubota S, Carvalho S, Pennington MW, Owens IS, Popescu NC: Thirteen UDPglucuronosyltransferase genes are encoded at the human UGT1 gene complex locus. Pharmacogenetics. 2001 Jun;11(4):357-68.
Pubmed: 11434514
Hillier LW, Graves TA, Fulton RS, Fulton LA, Pepin KH, Minx P, Wagner-McPherson C, Layman D, Wylie K, Sekhon M, Becker MC, Fewell GA, Delehaunty KD, Miner TL, Nash WE, Kremitzki C, Oddy L, Du H, Sun H, Bradshaw-Cordum H, Ali J, Carter J, Cordes M, Harris A, Isak A, van Brunt A, Nguyen C, Du F, Courtney L, Kalicki J, Ozersky P, Abbott S, Armstrong J, Belter EA, Caruso L, Cedroni M, Cotton M, Davidson T, Desai A, Elliott G, Erb T, Fronick C, Gaige T, Haakenson W, Haglund K, Holmes A, Harkins R, Kim K, Kruchowski SS, Strong CM, Grewal N, Goyea E, Hou S, Levy A, Martinka S, Mead K, McLellan MD, Meyer R, Randall-Maher J, Tomlinson C, Dauphin-Kohlberg S, Kozlowicz-Reilly A, Shah N, Swearengen-Shahid S, Snider J, Strong JT, Thompson J, Yoakum M, Leonard S, Pearman C, Trani L, Radionenko M, Waligorski JE, Wang C, Rock SM, Tin-Wollam AM, Maupin R, Latreille P, Wendl MC, Yang SP, Pohl C, Wallis JW, Spieth J, Bieri TA, Berkowicz N, Nelson JO, Osborne J, Ding L, Meyer R, Sabo A, Shotland Y, Sinha P, Wohldmann PE, Cook LL, Hickenbotham MT, Eldred J, Williams D, Jones TA, She X, Ciccarelli FD, Izaurralde E, Taylor J, Schmutz J, Myers RM, Cox DR, Huang X, McPherson JD, Mardis ER, Clifton SW, Warren WC, Chinwalla AT, Eddy SR, Marra MA, Ovcharenko I, Furey TS, Miller W, Eichler EE, Bork P, Suyama M, Torrents D, Waterston RH, Wilson RK: Generation and annotation of the DNA sequences of human chromosomes 2 and 4. Nature. 2005 Apr 7;434(7034):724-31. doi: 10.1038/nature03466.
Pubmed: 15815621
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