The effect of granisetron on in vitro metabolism of doxorubicin, irinotecan and etoposide

ABSTRACT

Objective: Doxorubicin, irinotecan and etoposide are all associated with the debilitating side-effects of nausea and vomiting, thereby necessitating concomitant antiemetic therapy. However, this may increase the potential for drug–drug interactions by inhibition or induction of the cytochrome P450 enzymes. A study was undertaken to investigate the effects of the 5-HT₃-receptor antagonist granisetron on the metabolism of doxorubicin, irinotecan and etoposide in vitro in human liver microsomal preparations.

Research design and methods: Doxorubicin, 20 µM, irinotecan, 10 µM, and etoposide, 50 µM, were incubated in the presence of granisetron, 0 nM, 20 nM, 200 nM and 2000 nM, in human liver microsomal preparations (250 µg). The levels of unchanged doxorubicin, irinotecan and etoposide in the incubation mixture were determined by high-performance liquid chromatography. Positive controls were ketoconazole, 20 µM, a potent inhibitor of CYP3A metabolism, for irinotecan and etoposide and quercitrin, 2 mM, a potent inhibitor of aldo-keto reductase, for doxorubicin.

Results: In the absence of granisetron, unchanged doxorubicin, irinotecan and etoposide levels decreased by 34.2 ± 5.5%, 21.3 ± 2.9% and 13.4 ± 1.6% of control, respectively. Ketoconazole prevented the breakdown of both irinotecan and etoposide, while quercitrin inhibited the breakdown of doxorubicin. Granisetron had no effect on the rate of reduction of doxorubicin, irinotecan or etoposide.

Conclusions: The results from this study suggest that granisetron neither inhibits nor induces the enzymes involved in the metabolism of doxorubicin, irinotecan or etoposide. Thus, granisetron can be used safely to treat nausea and vomiting induced by these agents with minimal risk of drug–drug interactions.

Key words: :

• CYP3A
• Doxorubicin
• Etoposide
• Granisetron
• Irinotecan