Identification of the major human hepatic and placental enzymes responsible for the biotransformation of glyburide

Olga L. Zharikova, Valentina Fokina, Tatiana Nanovskaya, Ronald A. Hill, Donald R. Mattison, Gary Hankins, Mahmoud Ahmed

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1483-1490
Number of pages8
JournalBiochemical Pharmacology
Volume78
Issue number12
DOIs
StatePublished - Dec 15 2009

Fingerprint

Forensic Anthropology
Glyburide
Biotransformation
Metabolites
Liver
Enzymes
Isoenzymes
Aromatase
Drug interactions
Cytochrome P-450 CYP3A
Pharmacokinetics
Microsomes
Drug Interactions
Placenta
Complementary DNA
Urine
Tissue
Plasmas
Pregnancy
Kinetics

Keywords

  • Enzymes
  • Glyburide
  • Glyburide metabolism
  • Human liver
  • Human placenta

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

Identification of the major human hepatic and placental enzymes responsible for the biotransformation of glyburide. / Zharikova, Olga L.; Fokina, Valentina; Nanovskaya, Tatiana; Hill, Ronald A.; Mattison, Donald R.; Hankins, Gary; Ahmed, Mahmoud.

In: Biochemical Pharmacology, Vol. 78, No. 12, 15.12.2009, p. 1483-1490.

Research output: Contribution to journalArticle

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AU - Hankins, Gary

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AB - 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.

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