Alpha interferon has no effect on lidocaine metabolism in the rat

Abstract

Interferons (IFN) inhibit activity of many isoenzymes of the hepatic microsomal cytochrome P-450 system. This inhibition is species specific. Lidocaine is metabolized by cytochrome P-450 III A 4. We investigated in the rat the effect of rat alpha-IFN on lidocaine elimination and on its extraction by the isolated perfused rat liver. To determine elimination, the femoral artery and vein were cannulated. 24 h later, the conscious rat was given lidocaine through the venous catheter and blood was drawn from the arterial catheter for lidocaine determination every 3 min for 20 min. 7 rats were pre-treated with intramuscular rat alpha-IFN 7.5 x 10(5) U, 24 h prior to the experiment and another 4 rats were given saline i.m. The lidocaine elimination rate constant was unchanged, 0.065 min-1 and 0.063 min-1 for the control and IFN groups, respectively. To investigate lidocaine extraction, the isolated perfused rat liver was used. Perfusate samples from the portal and hepatic veins were drawn at 2 min intervals for 20 min, and lidocaine extraction determined. Extraction was determined in two groups of 6 rats each. The first group served as control and these rats were injected with saline only, while in the second group, the rats were pre-treated with rat alpha-IFN 7.5 x 10(5) U. Lidocaine extraction by the isolated perfused rat liver remained unchanged, 97.0 +/- 0.7% and 94.0 +/- 2.4% in the control and IFN treated groups, respectively. It is concluded that the rat alpha-IFN affects neither the elimination nor the extraction of lidocaine.

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

“…Since intravenously administrated DTX is mainly eliminated in bile and, to a lesser extent, by the kidneys (Bissery et al 1995), the absence of modification of intravenous DTX pharmacokinetics in the treated groups agrees with our previous findings, where we showed that IFN-a (4 MIU kg −1 ) had no effect on hepatic and renal P-gp expression (Ben Reguiga et al 2005). In addition, even if DTX is extensively metabolized by hepatic CYPs in rats compared with humans (Vaclavikova et al 2003), several studies indicate that rhIFN-a does not modify CYP3A activity in rats (Craig et al 1989;Melzer et al 1994;Goerz et al 1995).…”

Modification of the P-Glycoprotein Dependent Pharmacokinetics of Digoxin in Rats by Human Recombinant Interferon-α

“…However, this hypothesis should be roughly excluded because several papers have yet shown that rhIFN-a has no effect on CYP 3A activity and liver metabolism in rat (23,51,52), and Western blot studies in liver has not shown any modification in P-gp expression after treatment with interferon (Fig. 4).…”

“…Interferonalpha (IFN-a), a member of the type 1 interferon family and which acts through different signaling pathways than IFN-g, is a widely used cytokine in antiviral and cancer therapeutics (20). In humans, IFN-a has been shown to interfere with the metabolism of many drugs by acting as a potent CYP inhibitor (21), whereas in rats it had no inhibitory effect on CYP activity (22,23) The impact of IFN-a on P-gp is not yet clear. In vitro, IFN-a increases sensitivity to doxorubicin in multidrug-resistant Chinese hamster ovary cells with an increase in P-gp expression and mdr-1 mRNA synthesis (24).…”