Multidrug resistance (MDR)-1-P-glycoprotein (P-gp) is a drug-transporting
protein that is abundantly present in biliary ductal cells and epithelial
cells lining the gastrointestinal tract. Here, we have determined the role
of P-gp in the metabolic disposition of the antineoplastic agent docetaxel
(Taxotere) in humans. Pharmacokinetic profiles were evaluated in five
cancer patients receiving treatment cycles with docetaxel alone (100 mg/m2
i.v. over a 1-h period) and in combination with a new potent inhibitor of
P-gp activity, R101933 (200-300 mg b.i.d.). The terminal disposition
half-life and total plasma clearance of docetaxel were not altered by
treatment with oral R101933 (P > or = 0.27). The cumulative fecal
excretion of docetaxel, however, was markedly reduced from 8.47 +/- 2.14%
(mean +/- SD) of the dose with the single agent to less than 0.5% in the
presence of R101933 (P = 0.0016). Levels of the major cytochrome P450
3A4-mediated metabolites of docetaxel in feces were significantly
increased after combination treatment with R101933 (P = 0.010), indicating
very prominent and efficient detoxification of reabsorbed docetaxel into
hydroxylated compounds before reaching the systemic circulation. It is
concluded that intestinal P-gp plays a principal role in the fecal
elimination of docetaxel by modulating reabsorption of the drug after
hepatobiliary secretion. In addition, the results indicate that inhibition
of P-gp activity in normal tissues by effective modulators, and the
physiological and pharmacological consequences of this treatment, cannot
be predicted based on plasma drug monitoring alone