Identification of glyburide metabolites formed by hepatic and placental microsomes of humans and baboons

Selvan Ravindran, Olga L. Zharikova, Ronald A. Hill, Tatiana N. Nanovskaya, Gary D.V. Hankins, Mahmoud S. Ahmed

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Glyburide (glibenclamide) is a second-generation sulfonylurea used for treatment of type-2 and gestational diabetes mellitus. To date, two glyburide metabolites have been identified in maternal urine: namely, 4-trans-hydroxycyclohexyl glyburide and 3-cis-hydroxycyclohexyl glyburide. The use of glyburide to treat gestational diabetes prompted us to investigate its metabolism by the placenta. The metabolism of glyburide by microsomal preparations from human and baboon placenta was compared with metabolism by their livers. The metabolites formed by the microsomes of the four tissues were identified by high-performance liquid chromatography-mass spectrometry using retention times, ion current (extracted at m/z 510), and selected-ion monitoring. The data obtained revealed the formation of six distinct hydroxylated derivatives of glyburide by each of the four microsomal preparations. However, the amounts of the six metabolites formed by the placentas were a fraction of that formed by the livers. Moreover, the relative quantities of each metabolite formed differed between species as well as between the two tissues. Also, the structure of the unidentified metabolites was determined by comparison with synthesized standards. These metabolites were identified as the 4-cis-hydroxycyclohexyl glyburide, 3-trans-hydroxycyclohexyl glyburide, and 2-trans-hydroxycyclohexyl glyburide. Therefore, one glyburide metabolite remains to be identified, but the data we obtained allowed us to suggest its structure.

Original languageEnglish (US)
Pages (from-to)1730-1737
Number of pages8
JournalBiochemical Pharmacology
Volume72
Issue number12
DOIs
StatePublished - Dec 15 2006

Keywords

  • Baboon placenta
  • Gestational diabetes
  • Glyburide
  • Human placenta
  • Mass spectrometry
  • Metabolism
  • Pregnancy

ASJC Scopus subject areas

  • Biochemistry
  • Pharmacology

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