Role of intestinal P-glycoprotein in the plasma and fecal disposition of docetaxel in humans.
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.
van Zuylen
L
L
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, The Netherlands. zuylen@onch.azr.nl
Verweij
J
J
Nooter
K
K
Brouwer
E
E
Stoter
G
G
Sparreboom
A
A
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001552:Benzazepines / Q000494:pharmacology; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003630:Daunorubicin / Q000493:pharmacokinetics; D000077143:Docetaxel; D018432:Drug Resistance, Multiple; D005243:Feces / Q000737:chemistry; D006207:Half-Life; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D006899:Mixed Function Oxygenases / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D011804:Quinolines / Q000494:pharmacology; D043823:Taxoids; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D001552:Benzazepines; D011804:Quinolines; D043823:Taxoids; D000077143:Docetaxel; D003577:Cytochrome P-450 Enzyme System; D006899:Mixed Function Oxygenases; C104464:CYP3A protein, human; D051544:Cytochrome P-450 CYP3A; C411474:laniquidar; D017239:Paclitaxel; D003630:Daunorubicin