title: The influence of aged garlic extract on the uptake of saquinavir and darunavir into HepG2 cells and rat liver slices.
abstract: Bioavailability and therapeutic outcome of treatment with HIV-protease inhibitors depends on intestinal and hepatic transporter-enzyme interplay. Liver transport of HIV protease inhibitors (saquinavir, darunavir) was assessed in the presence of aged garlic extract, because the HIV-infected often consume garlic supplements together with prescribed therapy. The in vitro uptake of both drugs into HepG2 cells and precision cut rat liver slices significantly increased in the presence of Pgp and MRP-2 inhibitor ritonavir. The incubation medium containing aged garlic extract caused significant inhibition of saquinavir efflux from HepG2 cells and precision cut liver slices, while the activity of darunavir efflux transporters in both liver models significantly increased. Due to opposite in vitro interactions observed between aged garlic extract and HIV protease inhibitors, darunavir and saquinavir most probably bind to different binding sites on one or both efflux transporters. Based on this study, coadministration of investigated compounds with garlic supplements could result in significant in vivo modification of hepatic transport-enzyme interplay, possibly leading to further bioavailability change.
authors.affiliation: Faculty of Pharmacy, University of Ljubljana, Askerceva 7, Ljubljana, Slovenia. katja.berginc@ffa.uni-lj.si
authors.forename: Katja
authors.initials: K
authors.lastname: Berginc
authors.forename: Jurij
authors.initials: J
authors.lastname: Trontelj
authors.forename: Albin
authors.initials: A
authors.lastname: Kristl
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D000069454:Darunavir; D004386:Duodenum; D005737:Garlic; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D056945:Hep G2 Cells; D041743:Herb-Drug Interactions; D006801:Humans; D008099:Liver / Q000166:cytology / Q000187:drug effects; D008297:Male; D026901:Membrane Transport Proteins / Q000378:metabolism*; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D019438:Ritonavir / Q000494:pharmacology; D019258:Saquinavir / Q000493:pharmacokinetics*; D013449:Sulfonamides / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000069454:Darunavir; D017320:HIV Protease Inhibitors; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D010936:Plant Extracts; D019438:Ritonavir; D019258:Saquinavir; D013449:Sulfonamides; C000715087:ABCC2 protein, human