Effect of Interleukin-2 on Intestinal P-glycoprotein Expression and Functionality in Mice

Veau, Céline; Faivre, Laurence; Tardivel, Sylviane; Soursac, Mireille; Banide, Hélène; Lacour, Bernard; Farinotti, Robert

doi:10.1124/jpet.302.2.742

Cited by 30 publications

(19 citation statements)

References 32 publications

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“…A potential explanation for this inconsistency could be the differences in transporter expression (5,53) and phosphorylated metabolite levels between PBMCs stimulated with phytohemagglutinin and interleukin-2 (8) and inactivated PBMCs. Probably due to the very slow phosphorylation in our experimental system with inactivated PBMCs, the intracellular FTC and TFV triphosphorylated metabolite concentrations were at about the lower limit of quantitation of our assay method used for NRTI triphosphates (44).…”

Section: Discussionmentioning

confidence: 99%

Combination of Tenofovir and Emtricitabine plus Efavirenz: In Vitro Modulation of ABC Transporter and Intracellular Drug Accumulation

Bousquet

Pruvost

Guyot

et al. 2009

Antimicrob Agents Chemother

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(multidrug resistance-associated protein), and OAT (organic anion transporter) expression in response to the treatments was quantified by semiquantitative real-time PCR. Cells treated with a double combination (FTC-TFV or TFV-EFV) or the triple combination (FTC-TFV-EFV) produced higher FTC and TFV intracellular concentrations than cells treated with FTC orTFV alone. However, no change in the EFV intracellular concentration was observed. FTC tended to induce abcc5 mRNA expression and EFV tended to induce abcc1 and abcc6 mRNA expression, whereas TFV tended to reduce mdr1, abcc1, abcc5, and abcc6 mRNA expression. Under these conditions, a decrease in the functionality of ABCC was observed, and this decrease was associated with the direct inhibitory actions of these drugs. This in vitro study reveals a benefit of the combination FTC-TFV-EFV in terms of the intracellular FTC and TFV concentrations and highlights the pharmacological mechanisms that lead to this effect.

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Section: Discussionmentioning

confidence: 99%

Combination of Tenofovir and Emtricitabine plus Efavirenz: In Vitro Modulation of ABC Transporter and Intracellular Drug Accumulation

Bousquet

Pruvost

Guyot

et al. 2009

Antimicrob Agents Chemother

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“…In the case of oral digoxin pharmacokinetics modification after rIL2 pretreatment, shown by Bonhomme-Faivre et al (2002) and Veau et al (2002), we can exclude the metabolism hypothesis. Indeed, the digoxin undergoes limited liver metabolism (Ͻ10%), and then a decrease in digoxin metabolism could not explain the observed re- Each concentration point is the mean Ϯ S.E.M.…”

Section: Resultsmentioning

confidence: 86%

“…As in humans, digoxin pharmacokinetics in mouse are mainly related to P-gp activity (excretion of digoxin by P-gp expressed in the membrane of renal and intestinal cells) and not dependent upon metabolism (Schinkel et al, 1997). Recent studies showed that a pretreatment with rIL2 (10 and 15 g/kg twice a day for 4 days) modified the pharmacokinetics of digoxin given orally in mice (Bonhomme-Faivre et al, 2002;Veau et al, 2002).…”

Section: P-gpmentioning

confidence: 99%

Effect of Recombinant Interleukin-2 Pretreatment on Oral and Intravenous Digoxin Pharmacokinetics and P-Glycoprotein Activity in Mice

Castagné¹,

Bonhomme-Faivre²,

Urien³

et al. 2004

Drug Metab Dispos

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:P-glycoprotein (P-gp) is an ATP-dependent efflux membrane transporter involved in many drug pharmacokinetics in humans. Decreasing its expression could enhance the bioavailability of substrates as digoxin. We have recently found that human recombinant interleukin-2 (rIL2) in vivo decreases P-gp expression in intestine and brain of mice and modifies oral digoxin pharmacokinetics. The aim of the study was to evaluate the involvement of bioavailability in the rIL2 pretreatment effect on digoxin pharmacokinetics by comparing oral and i.v. digoxin pharmacokinetics before and after rIL2 pretreatment (10 g/kg). We also tried to show the possible effect of a low rIL2 dose (1 g/kg) pretreatment on oral digoxin pharmacokinetics. First, adult Swiss mice received a single oral or i.v. dose of digoxin (0.03 mg/kg). Two weeks later, the same animals were treated by rIL2 i.p. twice a day (10 g/kg) for 4 days and received digoxin again at day 5. As well, another group received oral digoxin (0.03 mg/kg) with a 1 g/kg rIL2 pretreatment. Blood was collected after digoxin administration with and without rIL2 pretreatment. Digoxin pharmacokinetics were described by a one-compartment model. The 10 g/kg rIL2 pretreatment did not modify i.v. digoxin pharmacokinetics, whereas oral digoxin pharmacokinetics were significantly modified by the 10 g/kg rIL2 pretreatment and not by the 1 g/kg rIL2 pretreatment. The decrease of P-gp activity, caused by rIL2 (10 g/kg), increased digoxin bioavailability. An increase in exposure and intracellular level of drugs is expected from rIL2 pretreatment.

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“…Previous studies showed that rIL-2 administered i.p. at 0.27 MIU inhibited intestinal P-gp activity by decreasing intestinal P-gp functionality in mice (Veau et al, 2002). In addition, it has been demonstrated that the coadministration of PLX with a P-gp inhibitor (MS-209) (Naito et al, 2002) caused an increase of AUC and C max without modifying the other pharmacokinetic parameters (Kimura et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that rIL-2 decreases MDR1 mRNA and P-gp expression in human colon carcinoma cultured cells (Stein et al, 1996) and in intestine and brain of Swiss mice (Bonhomme-Faivre et al, 2002). Furthermore, we have shown previously that rIL-2 decreases rhodamine transport through the reversed gut sac of Swiss mice (Veau et al, 2002). In addition, rIL-2 pretreatment increased PLX efficacy measured by the significant decrease of s.c. tumor growth and lung metastasis number in the Lewis lung carcinoma model (Hosten et al, 2006).…”

mentioning

confidence: 91%

Effect of Interleukin-2 Pretreatment on Paclitaxel Absorption and Tissue Disposition after Oral and Intravenous Administration in Mice

Hosten

Abbara²,

Petit³

et al. 2008

Drug Metab Dispos

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ABSTRACT:The aim of the present study was to investigate the effects of recombinant interleukin (rIL)-2 treatment on paclitaxel (PLX) pharmacokinetics in the plasma and tissue of Lewis lung carcinomabearing mice (lung tissues and s.c. tumors). PLX pharmacokinetics studies were conducted after oral and i.v. administration of 15 and 4 mg/kg, respectively, either alone or after 3 days of rIL-2 pretreatment. The noncompartmental approach was used to determine the mean pharmacokinetic parameters using WinNonlin software (Pharsight, Mountain View, CA). The influence of rIL-2 pretreatment on physiological P-glycoprotein (P-gp) expression in lung and intestine was investigated by Western blot analysis. After oral administration of PLX, areas under the curve (AUC) in plasma, lung, and s.c. tumors were significantly higher (2.98, 2.66, and 3.41-fold, respectively) in the rIL-2 ؉ PLX group as compared with the PLX group. However, no significant effect of rIL-2 pretreatment was observed in plasma or lung following i.v. administration of PLX. PLX AUC in s.c. tumors was significantly higher (1.37-fold) with rIL-2 pretreatment as compared with the PLX-alone group after i.v. injection. Pretreatment with rIL-2 appeared to have no effect on PLX plasma terminal half-life when PLX was administered orally or i.v. However, prolongation of PLX terminal half-life estimated from lung and s.c. tumors data had been observed. Increased PLX tissue absorption in the rIL-2-pretreated group may be explained by a decrease of P-gp expression in the intestines and lung or decreased functionality due to rIL-2. Oral administration allowed the targeted tissues a much higher PLX exposure as compared with i.v. administration.

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Effect of Interleukin-2 on Intestinal P-glycoprotein Expression and Functionality in Mice

Cited by 30 publications

References 32 publications

Combination of Tenofovir and Emtricitabine plus Efavirenz: In Vitro Modulation of ABC Transporter and Intracellular Drug Accumulation

Combination of Tenofovir and Emtricitabine plus Efavirenz: In Vitro Modulation of ABC Transporter and Intracellular Drug Accumulation

Effect of Recombinant Interleukin-2 Pretreatment on Oral and Intravenous Digoxin Pharmacokinetics and P-Glycoprotein Activity in Mice

Effect of Interleukin-2 Pretreatment on Paclitaxel Absorption and Tissue Disposition after Oral and Intravenous Administration in Mice

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