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Pharmacokinetics

Alteration of pharmacokinetics of cyclophosphamide and suppression of the cytochrome P450 genes by ciprofloxacin

Bone Marrow Transplantation volume 31, pages 197–203 (2003)Cite this article

Summary:

Recently, it has been reported that prophylactic administration of ciprofloxacin during cyclophosphamide (CY) conditioning was a high-risk factor for relapse in patients undergoing allogeneic BMT. In the present study, we investigated the possible mechanisms of this interaction in male Sprague–Dawley rats. The kinetics of CY and its active 4-OH-CY metabolite were determined, after 3 days pretreatment with ciprofloxacin (200 mg/kg) and compared to control rats without treatment. CY was administered as a high or low single intravenous dose (150 and 90 mg/kg, respectively). The expression of the CYP2B1, CYP2B2, CYP2C11, CYP3A1 and CYP3A2 genes was evaluated by SYBR Green I Dye real-time PCR for quantification of mRNA. The administration of ciprofloxacin resulted in a significant increase in the AUC (P=0.007) and a significant decrease in clearance (P=0.007) when CY was given as a high dose. In accordance, the metabolic ratio (AUC4-OH-CY/AUCCY) was significantly lower (P=0.007) compared to that found in the control group. Ciprofloxacin significantly suppressed gene expression of CYP2C11 (P=0.01) and CYP3A1 (P=0.04); however, no effect was observed on the gene expression of CYP3A2, CYP2B1 and CYP2B2. Our study revealed that ciprofloxacin interacts with CY and suppressed relevant cytochromes P450 at the transcriptional level. This study may have a great clinical impact when ciprofloxacin is used in therapy.

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Acknowledgements

This study was supported by grants from the Swedish Cancer Society, Swedish Medical Research Council (04496), Stiftelsen Tornspiran (Sweden) and Anders Otto Swärds Stiftelse, Grant no. PROJ01/059 from Swedish Children Cancer Society and Grant no. 02:119 from the Stockholm's Cancer Foundation (Sweden).

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Authors and Affiliations

  1. Division of Clinical Pharmacology, Department of Medical Laboratory Sciences and Technology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden

    H-J Xie, S Lundgren, L Meurling & A Rane

  2. Division of Hematology, Department of Medicine, Laboratory of Hematoglogy, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden

    L Griskevicius, U Broberg, C Paul & M Hassan

  3. Division of Transplantation Surgery, Department of Surgery, Anesthesiology, Radiology and Orthopedic Surgery, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden

    S Carlens

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Xie, HJ., Griskevicius, L., Broberg, U. et al. Alteration of pharmacokinetics of cyclophosphamide and suppression of the cytochrome P450 genes by ciprofloxacin. Bone Marrow Transplant 31, 197–203 (2003). https://doi.org/10.1038/sj.bmt.1703815

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