Abstract
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 l−1 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.
Footnotes
-
This work was supported in part by Chiron Laboratories (Suresnes, France).
- Abbreviations:
- Pgp
- P-glycoprotein
- mdr
- multidrug resistance
- HIV
- human immunodeficiency virus
- IL2
- interleukin-2
- rIL2
- human recombinant interleukin-2
- MRP
- multidrug resistance-associated protein
- PBST
- phosphate-buffered saline-Tween 20
- PCR
- polymerase chain reaction
- AUC
- area under curve
- CL
- clearance
- F
- oral drug bioavailability
- Vd
- volume of distribution
- MRT
- mean resident time
- MIU
- million international units
- RT
- reverse transcription
- P450
- cytochrom P450
- Received September 4, 2001.
- Accepted March 10, 2002.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|