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. ThioTEPA inhibits the bioactivation of cyclophosphamide, and platinum drugs are known to interfere with the hepatic metabolism of several anticancer drugs. 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 biotransformation of thioTEPA.


METHODS
The possible inhibition of the metabolism of thioTEPA to TEPA was investigated in human microsomes. Influences on the conversion of thioTEPA to monoglutathionylthioTEPA, was studied by the incubation of thioTEPA with glutathione and glutathione S-transferase.


RESULTS
No inhibition of the metabolism of thioTEPA to form TEPA was observed for cyclophosphamide and carboplatin, or any other co-medicated drug (ciproflocaxin, amphotericin B, itraconazol, fluconazol, ondansetron, dexamethasone, granisetron, aciclovir, ranitidine, lorazepam). The conversion of thioTEPA to monoglutathionylthioTEPA was inhibited by cyclophosphamide, itraconazol, amphotericin B and ondansetron with IC50 values of 58, 256, 55 and 40 mM, respectively, which are far higher than therapeutic drug levels.


CONCLUSIONS
No clinically relevant drug-drug interactions occur in the CTC regimen as applied in our Institute.
Utrecht University, Department of Pharmaceutical Analysis, The Netherlands. M.J.vanMaanen@pharm.uu.nl
M J
MJ
van Maanen
A D
AD
Huitema
J H
JH
Beijen
D000111:Acetylcysteine / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001711:Biotransformation / Q000187:drug effects; D016190:Carboplatin / Q000494:pharmacology*; D003520:Cyclophosphamide / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008861:Microsomes / Q000187:drug effects* / Q000378:metabolism; D013852:Thiotepa / Q000378:metabolism*; D013721:Triethylenephosphoramide / Q000378:metabolism*
D000970:Antineoplastic Agents; D003520:Cyclophosphamide; D003577:Cytochrome P-450 Enzyme System; D013852:Thiotepa; D016190:Carboplatin; D005978:Glutathione; D013721:Triethylenephosphoramide; D000111:Acetylcysteine