Modification of the P-glycoprotein dependent pharmacokinetics of digoxin in rats by human recombinant interferon-alpha.
OBJECTIVE
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) 10(6), 2.10(6), or 4.10(6) IU kg(-1), s.c.), whereas pegylated-IFN-alpha (ViraferonPeg), 29 microg kg(-1)) was given s.c. three times a week. Rats were then given digoxin (32 microg 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 microg L(-1), p < 0.01 and 550 +/- 97 min microg L(-1), p < 0.001, respectively, vs. 286 +/- 111 min microg 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.


CONCLUSIONS
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.
Ben Reguiga
Makrem
M
Department of Clinical Pharmacy (UPRES 2706), Faculty of Pharmacy Paris XI, 92296 Châtenay-Malabry, France.
Bonhomme-Faivre
Laurence
L
Orbach-Arbouys
Simone
S
Farinotti
Robert
R
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D000818:Animals; D019540:Area Under Curve; D001682:Biological Availability; D015153:Blotting, Western; D004077:Digoxin / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000494:pharmacology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D004077:Digoxin