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The orally administered P-glycoprotein inhibitor R101933 does not alter the plasma pharmacokinetics of docetaxel
The orally administered P-glycoprotein inhibitor R101933 does not alter the plasma pharmacokinetics of docetaxel
This Phase I study was performed to assess the feasibility of combining
docetaxel with the new P-glycoprotein inhibitor R101933 and to determine
the dose limiting toxicity of this combination. Fifteen patients received
oral R101933 alone at a dose escalated from 200 to 300 mg twice daily
(b.i.d.; cycle 0), an escalating i.v. dose of docetaxel (60, 75, and 100
mg/m2) as a 1-h infusion (cycle 1), and the combination (cycle 2 and
further). Dose limiting toxicity consisting of mucositis and neutropenic
fever was reached at the combination of docetaxel, 100 mg/m2, and R101933,
300 mg b.i.d., and the maximum tolerated dose was established at
docetaxel, 100 mg/m2, and R101933, 200 mg b.i.d. Plasma concentrations of
R101933 achieved in patients were in the same range as required in
preclinical rodent models to overcome paclitaxel resistance. The plasma
pharmacokinetics of docetaxel were not influenced by the R101933 regimen
at any dose level tested, as indicated by plasma clearance values of 26.5
+/- 7.78 liters/h/m2 and 23.4 +/- 4.52 liters/h/m2 (P = 0.15) in cycles 1
and 2, respectively. These findings indicate that the contribution of a
P-glycoprotein inhibitor to the activity of anticancer chemotherapy can
now be assessed in patients for the first time independent of its effect
on drug pharmacokinetics
The orally administered P-glycoprotein inhibitor R101933 does not alter the plasma pharmacokinetics of docetaxel
Inhibition of pancreaticobiliary secretion by loperamide in humans.
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Simultaneous determination of fentanyl and alfentanil in rat tissues by capillary column gas chromatography
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