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

Abstract

Abstract Interferon-α (IFN-α) inhibits intestinal P-glycoprotein (P-gp) expression in rats. In the present study, the effects of repeated pre-treatment with recombinant human INF-α (rhIFN-α) 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-α for 8 days (4MIUkg−1, once daily) or with pegylated-IFN-α (ViraferonPeg; 60 μg kg−1, Days 1, 4 and 7). The rats were then distributed into subgroups (n = 5–6) according to the pre-treatment type, and received one dose of [14C]DTX (20 mg kg−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-αboth increased DTX oral bioavailability parameters: Cmax (17.0 ± 4.0 μgL−1 (P < 0.02) and 18 ± 5.5 μg L−1 (P < 0.05), respectively, vs 7.4 ± 2.5 μ g L−1 for the control) and AUC (0.036 ± 0.010 μg h mL−1 (P < 0.01) and 0.033 ± 0.009 μgh mL−1(P < 0.01), respectively, versus 0.012 ± 0.004 μghmL−1 for the control). IFN-α 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-αdid not affect intravenous DTX pharmacokinetics and it had a limited effect on tissue distribution at 240 min. [14C]DTX was decreased in intestine and enhanced in brain in both pre-treated groups. rhIFN-α modified the P-gp-dependent pharmacokinetics of DTX, limited its intestinal efflux and markedly enhanced its oral bioavailability.