Fluoroquinolones have been considered to be relatively well-tolerated and safe drugs, but gastrointestinal disorders and central nervous system events are the most common adverse effects. The fluoroquinolones are subjected to extensive metabolism and active metabolites can increase the risk of adverse reactions. Many interactions among drugs are due to metabolism through CYP 3A4/5 enzymes. The most expression of this emoprotein is in liver and in the small intestine. The presence of these compounds at intestinal level, at high concentration and/or for prolonged periods of time, suggested a potential risk of inducing toxic effects. On the basis of correlation with adverse reactions at skin level (phototoxicity) we evaluated a possible DNA damage in the gut and in the peripheral blood lymphocytes. The aim of this work is to assess in animals and in human subjects cellular damage (enterocytes and lymphocytes) and to verify changes in CYPs after repeated treatments. The expression of CYPs was determined by W.B. Lymphocyte and intestinal mucosa DNA damage was evaluated by Comet assay: the parameters were tail moment (TM), tail intensity (TI) and tail length (TL). The ciprofloxacin (Cp) and moxifloxacin (Mx) oral doses were 15 mg/kg/day and 10 mg/kg/day for levofloxacin (Lv) and gemifloxacin (Gm). Preliminary results in rat indicate that the levels of CYP 1A1/2 and CYP 2B1/2 are not modified by treatments, whereas CYP 3A4/5 is increased after three and nine days (Lv>Cp>Gm>Mx). It interesting to note that the rise is overall due to the protein 3A5 (60% circa). The rat lymphocyte DNA damage is present with Gm after three and nine days. The treatment with Lv induces a significant increase in TM and TL only after the ninth dose. The rat lymphocytes do not reveal any DNA damage with Cp and Mx. The intestinal cells show cytotoxicity with Lv treatment after nine doses and with Cp after three and nine doses. Data obtained in human lymphocytes indicate that Cp (500 mg/day) induces an increase in TI and TM, only after repeated doses. Preliminary data indicate that the fluoroquinolones show interesting differences in their toxicological profile either blood or intestinal levels. Supported by grant n° 2001058114–002 (MIUR- COFIN 2001)

Evaluations of CYP 3A 4/5 and DNA damage in rat enterocytes and in human and rat lymphocytes by fluoroquinolones

FRACASSO, Maria Enrica;FRANCESCHETTI, Paola;DORIA, Denise;BENINI, Anna;BERTAZZONI MINELLI, Elisa
2003-01-01

Abstract

Fluoroquinolones have been considered to be relatively well-tolerated and safe drugs, but gastrointestinal disorders and central nervous system events are the most common adverse effects. The fluoroquinolones are subjected to extensive metabolism and active metabolites can increase the risk of adverse reactions. Many interactions among drugs are due to metabolism through CYP 3A4/5 enzymes. The most expression of this emoprotein is in liver and in the small intestine. The presence of these compounds at intestinal level, at high concentration and/or for prolonged periods of time, suggested a potential risk of inducing toxic effects. On the basis of correlation with adverse reactions at skin level (phototoxicity) we evaluated a possible DNA damage in the gut and in the peripheral blood lymphocytes. The aim of this work is to assess in animals and in human subjects cellular damage (enterocytes and lymphocytes) and to verify changes in CYPs after repeated treatments. The expression of CYPs was determined by W.B. Lymphocyte and intestinal mucosa DNA damage was evaluated by Comet assay: the parameters were tail moment (TM), tail intensity (TI) and tail length (TL). The ciprofloxacin (Cp) and moxifloxacin (Mx) oral doses were 15 mg/kg/day and 10 mg/kg/day for levofloxacin (Lv) and gemifloxacin (Gm). Preliminary results in rat indicate that the levels of CYP 1A1/2 and CYP 2B1/2 are not modified by treatments, whereas CYP 3A4/5 is increased after three and nine days (Lv>Cp>Gm>Mx). It interesting to note that the rise is overall due to the protein 3A5 (60% circa). The rat lymphocyte DNA damage is present with Gm after three and nine days. The treatment with Lv induces a significant increase in TM and TL only after the ninth dose. The rat lymphocytes do not reveal any DNA damage with Cp and Mx. The intestinal cells show cytotoxicity with Lv treatment after nine doses and with Cp after three and nine doses. Data obtained in human lymphocytes indicate that Cp (500 mg/day) induces an increase in TI and TM, only after repeated doses. Preliminary data indicate that the fluoroquinolones show interesting differences in their toxicological profile either blood or intestinal levels. Supported by grant n° 2001058114–002 (MIUR- COFIN 2001)
CYP 3A 4/5, DNA damage, rat enterocytes, human and rat lymphocytes, fluoroquinolones
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11562/958392
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