Are there any known interactions between ciprofloxacin and cyclophosphamide?/nAt the transplantatio

Fråga: Are there any known interactions between ciprofloxacin and cyclophosphamide?

At the transplantation unit of Huddinge Hospital, it is noted that there is a higher incidence of rejection observed in bone marrow transplanted leukaemia patients, if treatment with ciprofloxacin is started during treatment with cyclophosphamide instead of after.

Sammanfattning: Several cytochrome P450 enzymes (CYP2B1, CYp2B6, CYP2C8, CYP2C9, CYP3A4) contribute to the metabolism of cyclophosphamide. Therefore, the clinical importance of this inhibition of CYP3A4 by ciprofloxacin is probably limited in the case of cyclophosphamide. We have found no data of an interaction between ciprofloxacin and cyclophosphamide.

Svar: Cyclophosphamide can be given orally or intravenously. It is well absorbed from the gastrointestinal tract with bioavailability greater than 75 per cent and excreted principally in urine as metabolites and some unchanged drug (1).

Ciprofloxacin inhibits CYP3A4 which causes some clinically important drug interactions with diazepam (2, 3) and cyclosporin A (4).

Though metabolism of cyclophosphamide has been extensively studied over the last 25 years, many questions remain unclear. Cyclophosphamide is a prodrug which requires bioactivation by CYP enzymes to finally yield the alkylating metabolite phosphoramide mustard and urotoxic metabolite acrolein. Besides this metabolic activation there are some other pathways which lead to inactive metabolites.

Another inactivation pathway of cyclophosphamide is the side chain oxidation which is also mediated by CYP enzymes (5). It has been recently shown that CYP3A4 catalyses this reaction (5). However, this reaction contributes only to a minor extent of the overall clearance of cyclophosphamide (5). Ciprofloxacin can increase the level of cyclophosphamide by inhibiting this step.

The main pathway of the metabolism of cyclophosphamide is the formation of 4-hydroxy cyclophosphamide and CYP2B1 (6); CYP2B6 (5); CYP2B6, CYP2C8, CYP2C9 (7); CYP2C8, CYP2C9, CYP3A4 (8) have been suggested to be the major enzymes involved in this ring oxidation. These findings appear to be questionable in the view of the fact that 15 per cent of Caucasian and 70 per cent of Japanese patients do not express CYP 2B6 at all (5). Interindividual differences may also play a role in the metabolism of cyclophosphamide. Although we have done a thorough literature search, we have found no conclusive data of an interaction between ciprofloxacin and cyclophosphamide.