Vol. 302, Issue 2, 742-750, August 2002

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

Celine Veau, Laurence Faivre, Sylviane Tardivel , Mireille Soursac, Helene Banide, Bernard Lacour and Robert Farinotti

Unité Propre de Recherche de l'Enseignement Supérieur 2706 (C.V., L.F., S.T., M.S., H.B., B.L., R.F.); Laboratoire du Métabolisme Minéral des Mamifères, Ecole Pratique Hautes Etudes-Physiologie, Faculté de Pharmacie, Châtenay-Malabry (S.T., B.L.); and Service de Pharmacie Clinique et des Biomatériaux, Hôpital Bichat, Paris, France (R.F.)

P-glycoprotein (Pgp), an active drug transporter expressed in enterocytes, can reduce intestinal absorption of drugs. Until now, interleukin-2 (IL2) has been reported as a Pgp modulator only in vitro. The present study examines the effects in vivo of IL2 after chronic treatment on intestinal Pgp protein expression and activity. This work also describes the effects of IL2 on the oral bioavailability of a Pgp substrate (digoxin) and of a Pgp/CYP3A cosubstrate (saquinavir). Human recombinant interleukin-2 (rIL2), administered to mice at 9 million international units/kg by intraperitoneal route twice daily for 4 days, led to a decrease in intestinal Pgp protein expression evaluated by Western blot with C219 antibody. In an in vitro everted gut sac model, rIL2 pretreatment decreased the Pgp-mediated transport of rhodamine 123 across mouse intestine by 37%. Moreover, rIL2 pretreatment markedly raised the area under the curve of orally administered digoxin from 3.5 ± 0.5 to 9.7 ± 1.5 mg min l¹ as a consequence of the reduction in intestinal Pgp activity. rIL2 treatment increased saquinavir bioavailability from 2.5 to 4.5%, showing that first-pass metabolism is not affected and that Pgp by itself has only a moderate effect on saquinavir oral bioavailability. In conclusion, rIL2 pretreatment reduces intestinal Pgp protein expression and activity in mice. However, the effect of such a treatment on drug bioavailability depends on the extent of their metabolism by CYP3A.