Effect of interferon-gamma on the pharmacokinetics of digoxin, a P-glycoprotein substrate, intravenously injected into the mouse.
P-glycoprotein (P-gp) is an efflux transporter with a wide substrate specificity that plays an important role in the disposition of drugs in the epithelial cells of various tissues, such as the gastrointestinal tract, liver, and kidney. One characteristic feature of this efflux transporter is that its expression and activity are modulated by various factors, including cytokines. Here, we investigated the effect of interferon-gamma (IFN-gamma) on the transport activity of P-gp and its expression in mice, since the cytokine is induced by various stimuli and capable of provoking a variety of cellular responses. Twenty-four hours after a single intraperitoneal injection of IFN-gamma (1 x 10(5) U), mice were intravenously injected with [3H]digoxin, a P-gp substrate, and its pharmacokinetics was examined. IFN-gamma pretreatment resulted in retardation of plasma elimination of the drug with a concomitant increase of its tissue levels in liver, kidney, and intestine. Furthermore, the excretion of [3H]digoxin into the urine and bile, but not into the intestinal lumen, was significantly reduced: the urinary and biliary excretion clearances in IFN-gamma-treated mice were 65 and 55%, respectively, of those clearances in untreated mice. However, the P-gp expression levels were only slightly reduced (20-30% reduction) by IFN-gamma treatment in the liver, kidney, or intestine on Western blot analysis. IFN-gamma also caused a slight down-regulation (20-30% reduction) in the expression of cytochrome P450 3A (CYP3A) on Western blot analysis. Thus, a more pronounced effect may be elicited by IFN-gamma for common substrates of P-gp and CYP3A.
Department of Biopharmaceutics and Drug Metabolism, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, Japan.
Hiroko
H
Kawaguchi
Yumi
Y
Matsui
Yoshihiko
Y
Watanabe
Yoshinobu
Y
Takakura
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D002316:Cardiotonic Agents / Q000493:pharmacokinetics; D051544:Cytochrome P-450 CYP3A; D004077:Digoxin / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007262:Infusions, Intravenous; D007371:Interferon-gamma / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism; D014018:Tissue Distribution; D014316:Tritium
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D002316:Cardiotonic Agents; D014316:Tritium; D004077:Digoxin; D007371:Interferon-gamma; D001189:Aryl Hydrocarbon Hydroxylases; D051544:Cytochrome P-450 CYP3A; D010089:Oxidoreductases, N-Demethylating