Decrease of gluconeogenesis by deramciclane is counteracted by cytochrome P450 inhibitors

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Abstract

The effect of deramciclane (EGIS-3886), a new anxiolytic drug, was investigated on carbohydrate metabolism in mouse isolated hepatocytes. Deramciclane is a substrate of hepatic cytochrome P450 enzymes. Its in-vivo administration has been shown to cause a dose-dependent liver glycogen depleting effect in dogs. Hepatocytes were prepared from male CFLP mice (fed or starved for 24 h) using the collagenase perfusion method. The cells were incubated in Krebs-Henseleit bicarbonate buffer at 37°C with constant bubbling of CO2/O2 (5:95, v/v). Glucose production of the cells was measured in deproteinized samples by a glucokinase-glucose 6-phosphate dehydrogenase method. Glycogen content of the cells was determined with the same method after hydrolysis. Glycogen breakdown in mouse isolated hepatocytes was not affected by deramciclane. Gluconeogenesis from alanine or pyruvate but not from fructose was inhibited by high concentrations (40 μM) of deramciclane. The inhibitory effect of deramciclane on glucose production (nmol min-1/106 cells) from alanine was inhibited by econazole (-0.97 ± 0.13 vs -2.21 ± 0.49, P <0.05, s.e.m., n = 5) or by SKF 525A (- 0.60 ± 0.21 vs -2.21 ± 0.49, P <0.02). Addition of deramciclane did not affect the level of cAMP or glutathione in isolated hepatocytes. The study shows that oxidative biotransformation of deramciclane decreases glucose formation from three carbon unit precursors without any direct effect on glycogen metabolism. We concluded that glycogen depletion by long-term deramciclane administration may be mediated by decreased gluconeogenesis caused by increased NADPH consumption upon oxidative metabolism of deramciclane.

Original languageEnglish
Pages (from-to)469-472
Number of pages4
JournalPharmaceutical Sciences
Volume3
Issue number9
Publication statusPublished - 1997

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Gluconeogenesis
Cytochrome P-450 Enzyme System
Glycogen
Hepatocytes
Glucose
Alanine
Econazole
deramciclane
Proadifen
Glucokinase
Liver Glycogen
Glucosephosphate Dehydrogenase
Anti-Anxiety Agents
Carbohydrate Metabolism
Collagenases
Bicarbonates
Biotransformation
Fructose
Pyruvic Acid
NADP

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

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title = "Decrease of gluconeogenesis by deramciclane is counteracted by cytochrome P450 inhibitors",
abstract = "The effect of deramciclane (EGIS-3886), a new anxiolytic drug, was investigated on carbohydrate metabolism in mouse isolated hepatocytes. Deramciclane is a substrate of hepatic cytochrome P450 enzymes. Its in-vivo administration has been shown to cause a dose-dependent liver glycogen depleting effect in dogs. Hepatocytes were prepared from male CFLP mice (fed or starved for 24 h) using the collagenase perfusion method. The cells were incubated in Krebs-Henseleit bicarbonate buffer at 37°C with constant bubbling of CO2/O2 (5:95, v/v). Glucose production of the cells was measured in deproteinized samples by a glucokinase-glucose 6-phosphate dehydrogenase method. Glycogen content of the cells was determined with the same method after hydrolysis. Glycogen breakdown in mouse isolated hepatocytes was not affected by deramciclane. Gluconeogenesis from alanine or pyruvate but not from fructose was inhibited by high concentrations (40 μM) of deramciclane. The inhibitory effect of deramciclane on glucose production (nmol min-1/106 cells) from alanine was inhibited by econazole (-0.97 ± 0.13 vs -2.21 ± 0.49, P <0.05, s.e.m., n = 5) or by SKF 525A (- 0.60 ± 0.21 vs -2.21 ± 0.49, P <0.02). Addition of deramciclane did not affect the level of cAMP or glutathione in isolated hepatocytes. The study shows that oxidative biotransformation of deramciclane decreases glucose formation from three carbon unit precursors without any direct effect on glycogen metabolism. We concluded that glycogen depletion by long-term deramciclane administration may be mediated by decreased gluconeogenesis caused by increased NADPH consumption upon oxidative metabolism of deramciclane.",
author = "M. Csala and G. B{\'a}nhegyi and L. Braun and I. Klebovich and J. Mandl",
year = "1997",
language = "English",
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journal = "Journal of Pharmacy and Pharmacology",
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T1 - Decrease of gluconeogenesis by deramciclane is counteracted by cytochrome P450 inhibitors

AU - Csala, M.

AU - Bánhegyi, G.

AU - Braun, L.

AU - Klebovich, I.

AU - Mandl, J.

PY - 1997

Y1 - 1997

N2 - The effect of deramciclane (EGIS-3886), a new anxiolytic drug, was investigated on carbohydrate metabolism in mouse isolated hepatocytes. Deramciclane is a substrate of hepatic cytochrome P450 enzymes. Its in-vivo administration has been shown to cause a dose-dependent liver glycogen depleting effect in dogs. Hepatocytes were prepared from male CFLP mice (fed or starved for 24 h) using the collagenase perfusion method. The cells were incubated in Krebs-Henseleit bicarbonate buffer at 37°C with constant bubbling of CO2/O2 (5:95, v/v). Glucose production of the cells was measured in deproteinized samples by a glucokinase-glucose 6-phosphate dehydrogenase method. Glycogen content of the cells was determined with the same method after hydrolysis. Glycogen breakdown in mouse isolated hepatocytes was not affected by deramciclane. Gluconeogenesis from alanine or pyruvate but not from fructose was inhibited by high concentrations (40 μM) of deramciclane. The inhibitory effect of deramciclane on glucose production (nmol min-1/106 cells) from alanine was inhibited by econazole (-0.97 ± 0.13 vs -2.21 ± 0.49, P <0.05, s.e.m., n = 5) or by SKF 525A (- 0.60 ± 0.21 vs -2.21 ± 0.49, P <0.02). Addition of deramciclane did not affect the level of cAMP or glutathione in isolated hepatocytes. The study shows that oxidative biotransformation of deramciclane decreases glucose formation from three carbon unit precursors without any direct effect on glycogen metabolism. We concluded that glycogen depletion by long-term deramciclane administration may be mediated by decreased gluconeogenesis caused by increased NADPH consumption upon oxidative metabolism of deramciclane.

AB - The effect of deramciclane (EGIS-3886), a new anxiolytic drug, was investigated on carbohydrate metabolism in mouse isolated hepatocytes. Deramciclane is a substrate of hepatic cytochrome P450 enzymes. Its in-vivo administration has been shown to cause a dose-dependent liver glycogen depleting effect in dogs. Hepatocytes were prepared from male CFLP mice (fed or starved for 24 h) using the collagenase perfusion method. The cells were incubated in Krebs-Henseleit bicarbonate buffer at 37°C with constant bubbling of CO2/O2 (5:95, v/v). Glucose production of the cells was measured in deproteinized samples by a glucokinase-glucose 6-phosphate dehydrogenase method. Glycogen content of the cells was determined with the same method after hydrolysis. Glycogen breakdown in mouse isolated hepatocytes was not affected by deramciclane. Gluconeogenesis from alanine or pyruvate but not from fructose was inhibited by high concentrations (40 μM) of deramciclane. The inhibitory effect of deramciclane on glucose production (nmol min-1/106 cells) from alanine was inhibited by econazole (-0.97 ± 0.13 vs -2.21 ± 0.49, P <0.05, s.e.m., n = 5) or by SKF 525A (- 0.60 ± 0.21 vs -2.21 ± 0.49, P <0.02). Addition of deramciclane did not affect the level of cAMP or glutathione in isolated hepatocytes. The study shows that oxidative biotransformation of deramciclane decreases glucose formation from three carbon unit precursors without any direct effect on glycogen metabolism. We concluded that glycogen depletion by long-term deramciclane administration may be mediated by decreased gluconeogenesis caused by increased NADPH consumption upon oxidative metabolism of deramciclane.

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