Role of intestinal P-glycoprotein in the plasma and fecal disposition of docetaxel in humans.

Abstract

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.

• Authors: L van Zuylen, J Verweij, K Nooter, E Brouwer, G Stoter, A Sparreboom
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 6 Issue 7 Pg. 2598-603 (Jul 2000) ISSN: 1078-0432 [Print] United States
• PMID: 10914699 (Publication Type: Journal Article)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• Antineoplastic Agents, Phytogenic
• Benzazepines
• Quinolines
• Taxoids
• Docetaxel
• Cytochrome P-450 Enzyme System
• Mixed Function Oxygenases
• CYP3A protein, human
• Cytochrome P-450 CYP3A
• laniquidar
• Paclitaxel
• Daunorubicin

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (antagonists & inhibitors, metabolism)
• Antineoplastic Agents, Phytogenic (blood, pharmacokinetics, therapeutic use)
• Benzazepines (pharmacology)
• Cytochrome P-450 CYP3A
• Cytochrome P-450 Enzyme System (metabolism)
• Daunorubicin (pharmacokinetics)
• Docetaxel
• Drug Resistance, Multiple
• Feces (chemistry)
• Half-Life
• Humans
• Intestinal Mucosa (metabolism)
• Metabolic Clearance Rate
• Mixed Function Oxygenases (metabolism)
• Neoplasms (drug therapy)
• Paclitaxel (analogs & derivatives, blood, pharmacokinetics, therapeutic use)
• Quinolines (pharmacology)
• Taxoids
• Tumor Cells, Cultured