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.
Department of Medical Oncology, Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital, The Netherlands. zuylen@onch.azr.nl
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van Zuylen
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Verweij
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Nooter
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Brouwer
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Stoter
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Sparreboom
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