Kinetics of glyburide metabolism by hepatic and placental microsomes of human and baboon

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

Research output: Contribution to journalArticle

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Abstract

Glyburide (glibenclamide) is under investigation for treatment of gestational diabetes. Two metabolites of glyburide have been previously identified in patients, namely, 4-trans-(M1) and 3-cis-(M2) hydroxycyclohexyl glyburide. Recently, the metabolism of glyburide by microsomes of liver and placenta from humans and baboons revealed the formation of four additional metabolites: 4-cis-(M2a), 3-trans-(M3), and 2-trans-(M4) hydroxycyclohexyl glyburide, and ethyl-hydroxy glyburide (M5). The aim of this investigation was to determine the kinetics for the metabolism of glyburide by cytochrome P450 (CYP) isozymes of human and baboon placental and hepatic microsomes. The metabolism of glyburide by microsomes from the four organs revealed saturation kinetics and apparent Km values between 4 and 12 μM. However, the rates for formation of the metabolites varied between organs and species. M1 was the major metabolite (36% of total), formed by human hepatic microsomes with Vmax of 80 ± 13 pmol mg protein-1 min-1, and together with M2, accounted for only 51% of the total. M5 was the major metabolite (87%) formed by human placental microsomes with Vmax of 11 pmol mg protein-1 min-1. In baboon liver, M5 had the highest rate of formation (Vmax 135 ± 32 pmol mg protein-1 min-1, 39% of total), and in its placenta, was M4 (Vmax 0.7 ± 0.1 pmol mg protein-1 min-1, 65%). The activity of human and baboon hepatic microsomes in metabolizing glyburide was similar, but the activity of human and baboon placental microsomes was 7% and 0.3% of their respective hepatic microsomes. The data obtained suggest that more than 1 CYP isozyme is responsible for catalyzing the hydroxylation of glyburide.

Original languageEnglish (US)
Pages (from-to)2012-2019
Number of pages8
JournalBiochemical Pharmacology
Volume73
Issue number12
DOIs
StatePublished - Jun 15 2007

Fingerprint

Enzyme kinetics
Papio
Glyburide
Microsomes
Metabolism
Liver
Metabolites
Human Activities
Cytochrome P-450 Enzyme System
Placenta
Isoenzymes
Proteins
Hydroxylation
Gestational Diabetes
Liver Microsomes
Medical problems

Keywords

  • Baboon liver
  • Baboon placenta
  • Drug metabolism
  • Enzyme kinetics
  • Glyburide (glibenclamide) metabolism
  • Human liver
  • Human placenta
  • Microsomal enzymes
  • Pregnancy

ASJC Scopus subject areas

  • Pharmacology

Cite this

Kinetics of glyburide metabolism by hepatic and placental microsomes of human and baboon. / Zharikova, Olga L.; Ravindran, Selvan; Nanovskaya, Tatiana; Hill, Ronald A.; Hankins, Gary; Ahmed, Mahmoud.

In: Biochemical Pharmacology, Vol. 73, No. 12, 15.06.2007, p. 2012-2019.

Research output: Contribution to journalArticle

Zharikova, Olga L. ; Ravindran, Selvan ; Nanovskaya, Tatiana ; Hill, Ronald A. ; Hankins, Gary ; Ahmed, Mahmoud. / Kinetics of glyburide metabolism by hepatic and placental microsomes of human and baboon. In: Biochemical Pharmacology. 2007 ; Vol. 73, No. 12. pp. 2012-2019.
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abstract = "Glyburide (glibenclamide) is under investigation for treatment of gestational diabetes. Two metabolites of glyburide have been previously identified in patients, namely, 4-trans-(M1) and 3-cis-(M2) hydroxycyclohexyl glyburide. Recently, the metabolism of glyburide by microsomes of liver and placenta from humans and baboons revealed the formation of four additional metabolites: 4-cis-(M2a), 3-trans-(M3), and 2-trans-(M4) hydroxycyclohexyl glyburide, and ethyl-hydroxy glyburide (M5). The aim of this investigation was to determine the kinetics for the metabolism of glyburide by cytochrome P450 (CYP) isozymes of human and baboon placental and hepatic microsomes. The metabolism of glyburide by microsomes from the four organs revealed saturation kinetics and apparent Km values between 4 and 12 μM. However, the rates for formation of the metabolites varied between organs and species. M1 was the major metabolite (36{\%} of total), formed by human hepatic microsomes with Vmax of 80 ± 13 pmol mg protein-1 min-1, and together with M2, accounted for only 51{\%} of the total. M5 was the major metabolite (87{\%}) formed by human placental microsomes with Vmax of 11 pmol mg protein-1 min-1. In baboon liver, M5 had the highest rate of formation (Vmax 135 ± 32 pmol mg protein-1 min-1, 39{\%} of total), and in its placenta, was M4 (Vmax 0.7 ± 0.1 pmol mg protein-1 min-1, 65{\%}). The activity of human and baboon hepatic microsomes in metabolizing glyburide was similar, but the activity of human and baboon placental microsomes was 7{\%} and 0.3{\%} of their respective hepatic microsomes. The data obtained suggest that more than 1 CYP isozyme is responsible for catalyzing the hydroxylation of glyburide.",
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AU - Hill, Ronald A.

AU - Hankins, Gary

AU - Ahmed, Mahmoud

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N2 - Glyburide (glibenclamide) is under investigation for treatment of gestational diabetes. Two metabolites of glyburide have been previously identified in patients, namely, 4-trans-(M1) and 3-cis-(M2) hydroxycyclohexyl glyburide. Recently, the metabolism of glyburide by microsomes of liver and placenta from humans and baboons revealed the formation of four additional metabolites: 4-cis-(M2a), 3-trans-(M3), and 2-trans-(M4) hydroxycyclohexyl glyburide, and ethyl-hydroxy glyburide (M5). The aim of this investigation was to determine the kinetics for the metabolism of glyburide by cytochrome P450 (CYP) isozymes of human and baboon placental and hepatic microsomes. The metabolism of glyburide by microsomes from the four organs revealed saturation kinetics and apparent Km values between 4 and 12 μM. However, the rates for formation of the metabolites varied between organs and species. M1 was the major metabolite (36% of total), formed by human hepatic microsomes with Vmax of 80 ± 13 pmol mg protein-1 min-1, and together with M2, accounted for only 51% of the total. M5 was the major metabolite (87%) formed by human placental microsomes with Vmax of 11 pmol mg protein-1 min-1. In baboon liver, M5 had the highest rate of formation (Vmax 135 ± 32 pmol mg protein-1 min-1, 39% of total), and in its placenta, was M4 (Vmax 0.7 ± 0.1 pmol mg protein-1 min-1, 65%). The activity of human and baboon hepatic microsomes in metabolizing glyburide was similar, but the activity of human and baboon placental microsomes was 7% and 0.3% of their respective hepatic microsomes. The data obtained suggest that more than 1 CYP isozyme is responsible for catalyzing the hydroxylation of glyburide.

AB - Glyburide (glibenclamide) is under investigation for treatment of gestational diabetes. Two metabolites of glyburide have been previously identified in patients, namely, 4-trans-(M1) and 3-cis-(M2) hydroxycyclohexyl glyburide. Recently, the metabolism of glyburide by microsomes of liver and placenta from humans and baboons revealed the formation of four additional metabolites: 4-cis-(M2a), 3-trans-(M3), and 2-trans-(M4) hydroxycyclohexyl glyburide, and ethyl-hydroxy glyburide (M5). The aim of this investigation was to determine the kinetics for the metabolism of glyburide by cytochrome P450 (CYP) isozymes of human and baboon placental and hepatic microsomes. The metabolism of glyburide by microsomes from the four organs revealed saturation kinetics and apparent Km values between 4 and 12 μM. However, the rates for formation of the metabolites varied between organs and species. M1 was the major metabolite (36% of total), formed by human hepatic microsomes with Vmax of 80 ± 13 pmol mg protein-1 min-1, and together with M2, accounted for only 51% of the total. M5 was the major metabolite (87%) formed by human placental microsomes with Vmax of 11 pmol mg protein-1 min-1. In baboon liver, M5 had the highest rate of formation (Vmax 135 ± 32 pmol mg protein-1 min-1, 39% of total), and in its placenta, was M4 (Vmax 0.7 ± 0.1 pmol mg protein-1 min-1, 65%). The activity of human and baboon hepatic microsomes in metabolizing glyburide was similar, but the activity of human and baboon placental microsomes was 7% and 0.3% of their respective hepatic microsomes. The data obtained suggest that more than 1 CYP isozyme is responsible for catalyzing the hydroxylation of glyburide.

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KW - Human placenta

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KW - Pregnancy

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