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

Abstract

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 ¼ 0.007) and a significant decrease in clearance (P ¼ 0.007) when CY was given as a high dose. In accordance, the metabolic ratio (AUC4-OH-CY/ AUCCY) was significantly lower (P ¼ 0.007) compared to that found in the control group. Ciprofloxacin significantly suppressed gene expression of CYP2C11 (P ¼ 0.01) and CYP3A1 (P ¼ 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. Bone Marrow Transplantation (2003Transplantation ( ) 31, 197-203. doi:10.1038 Keywords: cyclophosphamide; ciprofloxacin; interaction; cytochrome P450; gene expression; bone marrow transplantation Cyclophosphamide (CY) is a prodrug, which requires hepatic biotransformation to exert its cytotoxic effect. 1 An alternative but minor pathway is the inactivation of CY and both pathways are dependent on cytochrome P450 enzymes. [2][3][4][5] In humans, CYP2B6 is the main catalyst of CY activation, along with the contribution from CYP2C, CYP3A4, and CYP2A6 isoenzymes. 5-7 CY inactivation is mostly catalysed by CYP3A4. 5 In noninduced male rats, the constitutively expressed CYP2C11 and CYP3A2 are the major enzymes involved in CY bioactivation, while the inducible CYP2B1 was shown to be a major catalyst of CY activation in induced rats. 2,4 Thus, in vivo or in vitro alteration of hepatic CYPs could change the rate and pattern of CY metabolism. 8 Concomitant use of CY with other drugs that are inhibitors or inducers of CYP2B, CYP2C, or CYP3A enzymes could cause interactions. [9][10][11][12] Ciprofloxacin is a DNA gyrase inhibitor used as an antibacterial drug. 13 This fluoroquinolone agent has gained widespread use in the treatment of a broad range of infections. 14 Investigations focused on drug interactions between ciprofloxacin and other drugs have been reported in recent years. Particularly, interactions between ciprofloxacin and drugs metabolised by the hepatic cytochrome P450 (CYP) system have attracted attention. 15 Studies with hepatic microsomes demonstrated that ciprofloxacin can decrease CYP3A-me...

The Effect of Repeated Administration of Cyclophosphamide on Cytochrome P450 2B in Rats

“…Group A was divided into two subgroups: group A-75 was treated with 75 mg/kg of CPA, whereas group A-150 received higher dose at 150 mg/kg. After each administration, three rats were killed 0.5 h after dosing, wherein Cmax of 4-OH-CPA is reached as we have reported in our previous study (26). Another three rats were killed 6 h after dosing (just before the next dose).…”

“…Untreated rats were used as controls. The dosage regimen used to study the autoinduction was based on the short half-lives of the parent compound CPA and its metabolite 4-OH-CPA (6,26).…”

“…The primers and PCR conditions used for CYP2B1, CYP2B2, CYP2C11, CYP3A1, and CYP3A2 amplifications were as described earlier (26). Briefly; the specific PCR conditions were optimized to produce PCR product with a minimum background.…”

RNA-Seq Quantification of Hepatic Drug Processing Genes in Germ-Free Mice

“…Endotoxin of common Gram-negative bacteria injected into rats decrease hepatic drug metabolism and cytochrome P450 expression (Ueyama et al, 2005). Oral antibiotics such as ciprofloxacin can alter the metabolism of other drugs coadministered to the host (Xie et al, 2003). Ciprofloxacin decreases the intestinal bacteria that make the secondary bile acid lithocholic acid, thus decreasing activation of the nuclear receptor pregnane X receptor and lowering Cyp3a expression in livers (Staudinger et al, 2001).…”

Pharmacokinetics of high-dose chemotherapy

“…The P450-mediated hydroxylation of CPA is subject to multiple drug-drug interactions at the microsomal level, such as those with ondansetron 19,20 or ciprofloxacin. 21 When administered at high doses, CPA displays nonlinear elimination kinetics, in a fashion dependent both on concentration and time. 22,23 A sevenfold intersubject difference in exposure to 4-OH-CPA was observed after CPA-TBI, where CPA is given first, and thus, is not subject to drug-radiation interactions.…”