Influence of co-medicated drugs on the biotransformation of thioTEPA to TEPA and thioTEPA-mercapturate

Background The combination of cyclophosphamide, thioTEPA and carboplatin is used in our Institute for. the treatment of breast or germ cell cancer. Th ioTEPA inhibits the bioactivation of cyclophosphamide, and platinum drugs a re known to interfere with the hepatic metabolism of several anticancer dru gs. Of the co-administered drugs to prevent unwanted side effects, some are enzyme inducers, cytochrome P450 inhibitors or substrates. The aim of this study was to investigate the influence of co-medicated drugs on the biotra nsformation of thioTEPA. Methods. The possible inhibition of the metabolism of thioTEPA to TEPA was investigated in human microsomes. Influences on th e conversion of thioTEPA to monoglutathionylthioTEPA, was studied by the in cubation of thioTEPA with glutathione and glutathione S-transfer-ase. Resul ts. No inhibition of the metabolism of thioTEPA to form TEPA was observed f or cyclophosphamide and carboplatin, pr any other comedicated drug (ciprofl ocaxin, amphotericin B, itraconazol, fluconazol, ondansetron, dexamethasone , granisetron, aciclovir; ranitidine, lorazepam). The conversion of thioTEP A to monoglutathionylthioTEPA was inhibited by cyclophosphamide, itraconazo l, amphotericin B and ondansetron with IC50 values of 58, 256, 55 and 40 mM , respectively, which are far higher than therapeutic drug levels. Conclusi on. No clinically relevant drug-drug interactions occur in the CTC regimen as applied in our Institute.