Clinical evidence,mechanism, importance and management
(a) Cimetidine,Dexamethasone, Diphenhydramine
On basis of an in vitro study using human liver slices and human liver microsomes it has been concluded that metabolism of paclitaxel is unlikely to be altered by cimetidine, dexamethasone or diphenhydramine, all of which are frequently given to prevent hypersensitivity reactions associated with paclitaxel or its vehicle, Cremophor (see b, below) (See reference number 1). The UK manufacturers say that paclitaxel clearance in patients is not affected by cimetidine premedication,(See reference number 2) although some authors(See reference number 3) have advised caution when using cimetidine with docetaxel or paclitaxel since cimetidine is known to affect cytochrome P450 isoenzyme CYP3A4, which is responsible, in part, for metabolism of these taxanes.
In vitro, Cremophor was found to inhibit metabolism of paclitaxel in human liver microsomes,(See reference number 1) which might be expected to increase its toxicity. The concentration used in in vitro study may be achieved clinically in patients given paclitaxel with Cremophor as vehicle (See reference number 4). This may be worth bearing in mind if other drugs formulated with Cremophor are given with paclitaxel.
An in vitro study in human bladder cancer cells found that antineoplastic effect of paclitaxel in combination with methotrexate was dependent on order of exposure to two drugs (See reference number 5)
Jamis-Dow CA,Klecker RW, Katki AG, Collins JM. Metabolism of taxol by humans and ratliver in vitro: a screen for drug interactions and interspecies differences. Cancer Chemother Pharmacol (1995) 36, 107–14.
Taxol (Paclitaxel). Bristol-Myers Squibb Pharmaceuticals Ltd. UK Summary of product characteristics,August 2005.
Clouse T,Geisler JP, Manahan KJ, Gudenkauf TJ, Linnemeier G, Wiemann MC. Should we be using cimetidine to premedicate patients receiving docetaxel or paclitaxel? Gynecol Oncol (2004) 95, 270–1.
Rischin D,Webster LK, Millward MJ, Linahan BM, Toner GC, Woollett AM, Morton CG, Bishop JF. Cremophor pharmacokinetics in patients receiving 3-, 6-, and 24-hour infusions ofpaclitaxel. J Natl Cancer Inst (1996) 88, 1297–1301.
Cos J,Bellmunt J, Soler C, Ribas A, Lluis JM, Murio JE, Margarit C. Comparative study ofsequential combinations of paclitaxel and methotrexate on a human bladder cancer cell line.Cancer Invest (2000) 18, 429–35.