Alteration of pharmacokinetics of cyclophosphamide and suppression of the cytochrome p450 genes by ciprofloxacin.
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.
Xie
H-J
HJ
Department of Medical Laboratory Sciences and Technology, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden.
Broberg
U
U
Griskevicius
L
L
Lundgren
S
S
Carlens
S
S
Meurling
L
L
Paul
C
C
Rane
A
A
Hassan
M
M
D000818:Animals; D002939:Ciprofloxacin / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000493:pharmacokinetics; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects
D065607:Cytochrome P-450 Enzyme Inhibitors; D007166:Immunosuppressive Agents; D012333:RNA, Messenger; C012358:4-hydroxycyclophosphamide; D002939:Ciprofloxacin; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System