Bioavailability and tissular distribution of docetaxel, a P-glycoprotein substrate, are modified by interferon-α in rats

Abstract

Interferon-alpha (IFN-alpha) inhibits intestinal P-glycoprotein (P-gp) expression in rats. In the present study, the effects of repeated pre-treatment with recombinant human INF-alpha (rhIFN-alpha) on oral and intravenous pharmacokinetics of a P-gp substrate, docetaxel (DTX; Taxotere) were investigated in a rat model. The bioavailability and distribution in different organs were also studied. Sprague-Dawley rats were subcutaneously pre-treated with either rhIFN-alpha for 8 days (4MIU kg(-1), once daily) or with pegylated-IFN-alpha (ViraferonPeg; 60 microg kg(-1), Days 1, 4 and 7). The rats were then distributed into sub-groups (n = 5-6) according to the pre-treatment type, and received one dose of [(14)C]DTX (20 mgkg(-1)) either orally or intravenously. Pharmacokinetics studies were then performed over 240 min, at the end of which tissues (intestine, liver, kidneys, lung, heart and brain) were immediately removed for radioactivity quantitation. Non-pegylated and pegylated IFN-alpha both increased DTX oral bioavailability parameters: C(max) (17.0+/-4.0 microg L(-1) (P < 0.02) and 18+/-5.5 microg L(-1) (P < 0.05), respectively, vs 7.4+/-2.5 microg L(-1) for the control) and AUC (0.036+/-0.010 microg h mL(-1) (P < 0.01) and 0.033+/-0.009 microg h mL(-1) (P < 0.01), respectively, versus 0.012+/-0.004 microg h mL(-1) for the control). IFN-alpha also delayed DTX absorption from 60 min in controls to about 95 min and 80 min in non-pegylated and pegylated treated animals, respectively. However, IFN-alpha did not affect intravenous DTX pharmacokinetics and it had a limited effect on tissue distribution at 240 min. [(14)C]DTX was decreased in intestine and enhanced in brain in both pre-treated groups. rhIFN-alpha modified the P-gp-dependent pharmacokinetics of DTX, limited its intestinal efflux and markedly enhanced its oral bioavailability.

Enhanced oral bioavailability of docetaxel by lecithin nanoparticles: preparation, in vitro, and in vivo evaluation

“…Docetaxel was reported as a P-glycoprotein substrate whose oral absorption is in part affected by P-glycoprotein efflux. 19 The permeability coefficient of the DTX-LNs was higher than that of the …”

Surface-modified solid lipid nanoparticles for oral delivery of docetaxel: enhanced intestinal absorption and lymphatic uptake

“…14,15 Several studies have shown that the oral bioavailability of docetaxel can be enhanced significantly by coadministration of Pgp and/or CYP3A inhibitors, such as cyclosporin A, ritonavir, interferon-alpha, and ontogen (ONT-093). 14,[16][17][18] However, the usefulness of these drugs in clinical practice is limited, especially for repeated administration, because of the risk of side effects, which include immunosuppression. 19 Solid lipid nanoparticles (SLNs) are submicron (50-1,000 nm) colloidal particulate systems composed of physiologically tolerable lipid components, which remain in the solid state at room temperature.…”

Pluronic P105/F127 mixed micelles for the delivery of docetaxel against Taxol-resistant non-small cell lung cancer: optimization and in vitro, in vivo evaluation

“…As a member of the taxanes family, DTX was shown to be a P-gp substrate. 27 By ATP depletion, along with inhibition of the P-gp ATPase activity, Pluronic P105 has been demonstrated to inhibit the P-gp mediated efflux of the drug, 28,29 which might explain the hypersensitizing effect of Pluronic copolymers in the drug-resistant A549/Taxol cells. However, further studies are required to determine whether Pluronic copolymers increase the cell's uptake of DTX and to examine how Pluronic copolymers mediate the efflux of DTX in drug-resistant A549/Taxol cells.…”