title: Identification of the major human hepatic and placental enzymes responsible for the biotransformation of glyburide.
abstract: One of the factors affecting the pharmacokinetics (PK) of a drug during pregnancy is the activity of hepatic and placental metabolizing enzymes. Recently, we reported on the biotransformation of glyburide by human hepatic and placental microsomes to six metabolites that are structurally identical between the two tissues. Two of the metabolites, 4-trans-(M1) and 3-cis-hydroxycyclohexyl glyburide (M2b), were previously identified in plasma and urine of patients treated with glyburide and are pharmacologically active. The aim of this investigation was to identify the major human hepatic and placental CYP450 isozymes responsible for the formation of each metabolite of glyburide. This was achieved by the use of chemical inhibitors selective for individual CYP isozymes and antibodies raised against them. The identification was confirmed by the kinetic constants for the biotransformation of glyburide by cDNA-expressed enzymes. The data revealed that the major hepatic isozymes responsible for the formation of each metabolite are as follows: CYP3A4 (ethylene-hydroxylated glyburide (M5), 3-trans-(M3) and 2-trans-(M4) cyclohexyl glyburide); CYP2C9 (M1, M2a (4-cis-) and M2b); CYP2C8 (M1 and M2b); and CYP2C19 (M2a). Human placental microsomal CYP19/aromatase was the major isozyme responsible for the biotransformation of glyburide to predominantly M5. The formation of significant amounts of M5 by CYP19 in the placenta could render this metabolite more accessible to the fetal circulation. The multiplicity of enzymes biotransforming glyburide and the metabolites formed underscores the potential for its drug interactions in vivo.
authors.affiliation: Department of Obstetrics & Gynecology, University of Texas Medical Branch, Galveston, TX, 77555-0587, USA.
authors.forename: Olga L
authors.initials: OL
authors.lastname: Zharikova
authors.forename: Valentina M
authors.initials: VM
authors.lastname: Fokina
authors.forename: Tatiana N
authors.initials: TN
authors.lastname: Nanovskaya
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Hill
authors.forename: Donald R
authors.initials: DR
authors.lastname: Mattison
authors.forename: Gary D V
authors.initials: GD
authors.lastname: Hankins
authors.forename: Mahmoud S
authors.initials: MS
authors.lastname: Ahmed
mesh_terms: D000906:Antibodies / Q000276:immunology; D003429:Cross Reactions; D003577:Cytochrome P-450 Enzyme System / Q000276:immunology / Q000378:metabolism; D005260:Female; D005905:Glyburide / Q000378:metabolism*; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008099:Liver / Q000201:enzymology*; D008861:Microsomes / Q000201:enzymology; D008862:Microsomes, Liver / Q000201:enzymology; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy
chemical_list: D000906:Antibodies; D007527:Isoenzymes; D003577:Cytochrome P-450 Enzyme System; D005905:Glyburide
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