title: Exploring food effects on indinavir absorption with human intestinal fluids in the mouse intestine.
abstract: Food can have a significant impact on the pharmacokinetics of orally administered drugs, as it may affect drug solubility as well as permeability. Since fed state conditions cannot easily be implemented in the presently available permeability tools, including the frequently used Caco-2 system, exploring food effects during drug development can be quite challenging. In this study, we investigated the effect of fasted and fed state conditions on the intestinal absorption of the HIV protease inhibitor indinavir using simulated and human intestinal fluids in the in situ intestinal perfusion technique in mice. Although the solubility of indinavir was 6-fold higher in fed state human intestinal fluids (FeHIF) as compared to fasted state HIF (FaHIF), the intestinal permeation of indinavir was 22-fold lower in FeHIF as compared to FaHIF. Dialysis experiments showed that only a small fraction of indinavir is accessible for absorption in FeHIF due to micellar entrapment, possibly explaining its low intestinal permeation. The presence of ritonavir, a known P-gp inhibitor, increased the intestinal permeation of indinavir by 2-fold in FaHIF, while there was no increase when using FeHIF. These data confirm that drug-food interactions form a complex interplay between solubility and permeability effects. The use of HIF in in situ intestinal perfusions holds great promise for biorelevant absorption evaluation as it allows to directly explore this complex solubility/permeability interplay on drug absorption.
authors: Laboratory for Drug Delivery and Disposition, KU Leuven, Campus Gasthuisberg, O&N 2, Herestraat 49, Box 921, B-3000 Leuven, Belgium. Electronic address: nico.holmstock@pharm.kuleuven.be.
authors: Nico
authors: N
authors: Holmstock
authors: Laboratory for Drug Delivery and Disposition, KU Leuven, Campus Gasthuisberg, O&N 2, Herestraat 49, Box 921, B-3000 Leuven, Belgium. Electronic address: tom.debruyn@pharm.kuleuven.be.
authors: Tom
authors: T
authors: De Bruyn
authors: Laboratory for Drug Delivery and Disposition, KU Leuven, Campus Gasthuisberg, O&N 2, Herestraat 49, Box 921, B-3000 Leuven, Belgium. Electronic address: jan.bevernage@pharm.kuleuven.be.
authors: Jan
authors: J
authors: Bevernage
authors: Laboratory for Drug Delivery and Disposition, KU Leuven, Campus Gasthuisberg, O&N 2, Herestraat 49, Box 921, B-3000 Leuven, Belgium. Electronic address: pieter.annaert@pharm.kuleuven.be.
authors: Pieter
authors: P
authors: Annaert
authors: Laboratory for Drug Delivery and Disposition, KU Leuven, Campus Gasthuisberg, O&N 2, Herestraat 49, Box 921, B-3000 Leuven, Belgium. Electronic address: raf.mols@pharm.kuleuven.be.
authors: Raf
authors: R
authors: Mols
authors: Department of Gastroenterology, University Hospitals Leuven, O&N, Herestraat 49, Box 701, B-3000 Leuven, Belgium. Electronic address: jan.tack@med.kuleuven.be.
authors: Jan
authors: J
authors: Tack
authors: Laboratory for Drug Delivery and Disposition, KU Leuven, Campus Gasthuisberg, O&N 2, Herestraat 49, Box 921, B-3000 Leuven, Belgium. Electronic address: patrick.augustijns@pharm.kuleuven.be.
authors: Patrick
authors: P
authors: Augustijns
mesh_terms: D000818:Animals; D001826:Body Fluids / Q000187:drug effects* / Q000378:metabolism; D018938:Caco-2 Cells; D005502:Food; D018565:Food-Drug Interactions; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D006801:Humans; D019469:Indinavir / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D007408:Intestinal Absorption / Q000187:drug effects*; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects*; D008297:Male; D051379:Mice; D012995:Solubility
chemical_list: D017320:HIV Protease Inhibitors; D019469:Indinavir