Abstract:
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) 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. 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.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
Ben Reguiga M,Bonhomme-Faivre L,Orbach-Arbouys S,Farinotti Rdoi
10.1007/s11095-005-7415-5subject
Has Abstractpub_date
2005-11-01 00:00:00pages
1829-36issue
11eissn
0724-8741issn
1573-904Xjournal_volume
22pub_type
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doi:10.1007/s11095-015-1782-3
更新日期:2016-01-01 00:00:00
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pub_type: 杂志文章
doi:10.1007/s11095-006-0067-2
更新日期:2006-06-01 00:00:00
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pub_type: 杂志文章
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更新日期:2015-07-01 00:00:00
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更新日期:2001-04-01 00:00:00
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更新日期:1988-11-01 00:00:00
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更新日期:1995-09-01 00:00:00
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更新日期:2017-07-01 00:00:00
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更新日期:1997-10-01 00:00:00
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更新日期:2020-05-21 00:00:00
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更新日期:2001-06-01 00:00:00
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更新日期:1996-09-01 00:00:00
abstract::The synthesis of an homologous series of new water-soluble derivatives of pilocarpine is described. The new compounds, referred to as soft quaternary salts, are water soluble by virtue of a cationic ammonium head and their lipophilicity can be modulated by manipulating the size and the nature of the substituent in the...
journal_title:Pharmaceutical research
pub_type: 杂志文章
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更新日期:1992-03-01 00:00:00
abstract::The pharmacokinetic parameters of leuprolide acetate, a potent analogue of LH-RH, were determined in rats and dogs after i.v. and s.c. dosing with leuprolide solution. The effective human dose of once-a-month injectable microspheres of leuprolide was estimated to be about 3.2 to 8.1 mg analogue/month using these param...
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更新日期:1991-06-01 00:00:00