The effect of granisetron on in vitro metabolism of paclitaxel and docetaxel.
OBJECTIVE
Paclitaxel and docetaxel are effective anticancer agents; however, these agents can be associated with the debilitating side effects of nausea and vomiting, thereby necessitatingthe administration of concomitant antiemetic agents. This increases the potential fordrug-drug interactionsthrough inhibition or induction of the cytochrome P450 (CYP) enzymes. The 5-HT3-receptor antagonists are currently regarded as the antiemetic 'gold standard' and this study was undertaken to investigate the effects of granisetron on the metabolism of paclitaxel and docetaxel in human liver microsomal preparations in vitro.


METHODS
Paclitaxel, 5 nM, and docetaxel, 1.25 nM, were incubated in the presence of granisetron, 0, 10, 100, and 1000 pM, in human liver microsomal preparations (500 microg). The levels of unchanged paclitaxel and docetaxel in the incubation mixture were determined by high-performance liquid chromatography. Ketoconazole, 10 nM, a potent inhibitor of CYP3A metabolism, served as a positive control.


RESULTS
In the absence of granisetron, unchanged paclitaxel and docetaxel levels measured were 27.2 +/- 2.8% and 44.3 +/- 4.0% of control, respectively. Ketoconazole prevented the breakdown of both paclitaxel and docetaxel, to the degree that no unchanged paclitaxel or docetaxel was detected in the incubation mixture. Granisetron had no effect on the rate of reduction of either paclitaxel or docetaxel; unchanged paclitaxel and docetaxel decreased to 25.0 +/- 1.5%, 26.4 +/- 1.0%, and 27.6 +/- 6.4%, and 44.2 +/- 1.5%, 41.2 +/- 4.1%, and 43.1 +/- 0.5%, respectively.


CONCLUSIONS
The results from this study suggest that granisetron neither inhibits nor induces the enzymes involved in the metabolism of paclitaxel or docetaxel. Thus, granisetron can be used safely as a supportive care agent to treat paclitaxel or docetaxel chemotherapy-induced nausea and vomiting with minimal risk of drug-drug interactions.
Watanabe
Yoh
Y
Department of Obstetrics and Gynecology, Kinki University School of Medicine, Osakasayama, Osaka, Japan. watanabe@med.kindai.ac.jp
Nakajima
Hiroyuki
H
Nozaki
Koichi
K
Hoshiai
Hiroshi
H
Noda
Kiichiro
K
D000704:Analysis of Variance; D000932:Antiemetics / Q000378:metabolism / Q000494:pharmacology*; D000935:Antifungal Agents / Q000378:metabolism / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000378:metabolism*; D002853:Chromatography, Liquid; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D000077143:Docetaxel; D005260:Female; D017829:Granisetron / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007654:Ketoconazole / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008862:Microsomes, Liver / Q000187:drug effects* / Q000201:enzymology; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000378:metabolism*; D043823:Taxoids
D000932:Antiemetics; D000935:Antifungal Agents; D000972:Antineoplastic Agents, Phytogenic; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System; D000077143:Docetaxel; D017829:Granisetron; D007654:Ketoconazole; D017239:Paclitaxel; D043823:Taxoids