Modification of the P-glycoprotein dependent pharmacokinetics of digoxin in rats by human recombinant interferon-α

Purpose. This study was conducted to investigate in vivo the impact of interferon-alpha (IFN)-alpha on P-glycoprotein (P-gp) activity in rats by studying how its administration modifies the bioavailability of digoxin, a fairly pure P-gp substrate. Methods. Human recombinant IFN-alpha was given to rats ( n = 5-7 per group) daily for 8 days at different doses (IntronA(R) 10(6), 2.10(6), or 4.10(6) IU kg(-1), s.c.), whereas pegylated-IFN-alpha (ViraferonPeg(R), 29 mu g kg(-1)) was given s.c. three times a week. Rats were then given digoxin ( 32 mu g kg(-1)) i.v. or orally. The pharmacokinetics of digoxin was studied. Intestinal P-gp expression was also examined. Results. The pharmacokinetics of i.v. administered digoxin was not modified by IFN-alpha, but a dose-dependent increase in areas under the curve (AUCs) was observed in the orally administered digoxin parameters in rats (AUCs: 392 +/- 83 min mu g L-1, p < 0.01 and 550 +/- 97 min mu g L-1, p < 0.001, respectively, vs. 286 +/- 111 min mu g L-1 for control). A decrease in P-gp expression in the ileum ( relative intensities: 0.70 +/- 0.19 for 4 Million International Unit (MIU) kg(-1) IFN-alpha-treated animals vs. 1.00 +/- 0.13 for controls, p < 0.05) and mainly in the jejunum ( relative intensities: 0.46 +/- 0.13 for 4 MIU kg(-1) IFN-alpha-treated animals vs. 1.00 +/- 0.08 for controls, p < 0.001) was observed. Conclusion. IFN-alpha induces in vivo a significant dose-dependent inhibitory effect on intestinal P-gp activity related to a local decrease in its expression, thereby predicting important clinical consequences when IFN-alpha and other P-gp substrates are associated.