Abstract
Oral treatment with ifosfamide results in dose-limiting encephalopathy. Methylene blue is effective in reversal and prophylaxis of this side effect. In the present study, the pharmacokinetics of ifosfamide after iv and po therapy in combination with prophylactic administration of methylene blue were investigated. Nine patients with metastatic non–small cell lung cancer were treated by a combination of ifosfamide (3 days), sodium 2-mercaptoethane sulfonate (4 days), and etoposide (8 days). Cycles were repeated every 28 days. Ifosfamide was administered orally, with the exception of one of the first two cycles, when it was administered as a short infusion (randomly assigned). The patients received methylene blue in doses of 50 mg po 3 times daily; an initial dose of 50 mg was given the evening before chemotherapy. Urine samples were collected over the entire treatment period, and concentrations of ifosfamide and its major metabolite, 2-chloroethylamine, were measured by gas liquid chromatography. By the same technique, 2- and 3-dechloroethylifosfamide were determined in plasma and urine. Overall alkylating activity in urine was assayed by reaction of the alkylating metabolites with 4-(4′-nitrobenzyl)-pyridine. The chemotherapeutic regimen was well-tolerated by all of the patients studied. There was no evidence of a shift in the metabolic pattern dependent on the route of administration. From the data, we conclude that methylene blue has a neuroprotective effect and that the pharmacokinetics of ifosfamide are not influenced by its comedication.
Footnotes
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Send reprint requests to: Christine Aeschlimann, Ph.D., Department of Clinical Pharmacology, University of Berne, Murtenstr. 35, CH-3010 Berne, Switzerland.
- Abbreviations used are::
- ifos
- ifosfamide
- mb
- methylene blue
- mesna
- sodium 2-mercaptoethane sulfonate
- 2-DCE
- 2-dechloroethylifosfamide
- 3-DCE
- 3-dechloroethylifosfamide
- NBP
- 4-(4′-nitrobenzyl)-pyridine
- 2-CIEA
- 2-chloroethylammonium chloride
- HPLC
- high-performance liquid chromatography
- AUC
- plasma concentration-time curve
- AUCpo
- AUCafter po administration of ifos
- AUCiv
- AUC after iv administration of ifos
- F
- mean bioavailability
- CL
- mean total body clearance
- Received September 5, 1997.
- Accepted February 17, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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