The inhibition of gluconeogenesis by gatifloxacin may contribute to its hypoglycaemic action.
The action of gatifloxacin, the broad-spectrum fluoroquinolone antibiotic commonly used in the therapy of various bacterial infections, was investigated in isolated rabbit hepatocytes and kidney-cortex tubules by measuring the activity of gluconeogenesis, a process that maintains whole body glucose homeostasis. The data show that in kidney-cortex tubules, application of gatifloxacin at up to 100 microM was followed by a marked accumulation of the drug in the intracellular milieu and a decrease in the rate of glucose formation from pyruvate by 20-50%. Gatifloxacin did not affect the rate of gluconeogenesis from either alanine + glycerol + octanoate or aspartate + glycerol + octanoate. At concentrations between 25 and 200 microM the drug decreased mitochondrial oxygen consumption by 20-45% with pyruvate + malate and ADP. As in the case of alpha-cyano-4-hydroxycinnamate, a well-established inhibitor of the mitochondrial pyruvate transporter, it diminished pyruvate uptake by both renal and hepatic mitochondria. The inhibitory action of gatifloxacin was less pronounced in hepatocytes where reduction in pyruvate-dependent glucose formation and mitochondrial respiration was by no more than 25%. The antibiotic did not influence mitochondrial oxygen consumption with glutamate + malate in either kidney-cortex or liver mitochondria. A differential substrate dependence of gatifloxacin action on gluconeogenesis and mitochondrial respiration combined with a decrease in pyruvate uptake by mitochondria suggest that the inhibitory action of this drug on gluconeogenesis might result from its impairment of pyruvate transport into mitochondria.
Drozak
Jakub
J
Department of Metabolic Regulation, Institute of Biochemistry, Faculty of Biology, University of Warsaw, ul. I. Miecznikowa 1, 02-096 Warszawa, Poland.
Miecznik
Anna
A
Jarzyna
Robert
R
Bryla
Jadwiga
J
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001219:Aspartate Aminotransferases / Q000097:blood; D001693:Biological Transport, Active / Q000187:drug effects; D003373:Coumaric Acids / Q000494:pharmacology; D024841:Fluoroquinolones / Q000494:pharmacology*; D000077734:Gatifloxacin; D005943:Gluconeogenesis / Q000187:drug effects*; D018698:Glutamic Acid / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007004:Hypoglycemic Agents; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000187:drug effects / Q000378:metabolism; D007684:Kidney Tubules / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008293:Malates / Q000378:metabolism; D008297:Male; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D011773:Pyruvates / Q000378:metabolism; D011817:Rabbits
D000900:Anti-Bacterial Agents; D003373:Coumaric Acids; D024841:Fluoroquinolones; D007004:Hypoglycemic Agents; D008293:Malates; D011773:Pyruvates; C007175:alpha-cyano-4-hydroxycinnamate; D018698:Glutamic Acid; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000077734:Gatifloxacin