title: Comparative effects on intestinal absorption in situ by P-glycoprotein-modifying HIV protease inhibitors.
abstract: OBJECTIVE
  P-glycoprotein (P-gp) is made responsible for the limited oral bioavailability of P-gp substrates like peptidic HIV protease inhibitors (PIs). With respect to combined application of two PIs in antiretroviral regimes, we first investigated the influences on intestinal saquinavir uptake using different PIs in in situ perfusion studies.
  
  
  METHODS
  Perfusion experiments were carried out in three intestinal segments with P-gp substrates talinolol and saquinavir using fixed concentrations of PIs and with each varying concentrations in the jejunum and ileum. Furthermore, cellular uptake of fluorescent P-gp substrate rhodamine-123 and MRP-substrate carboxyfluorescein has each been quantified in P-gp and MRP-expressing cells by flow cytometry under co-administration of PIs.
  
  
  RESULTS
  Increase of calculated permeabilities of P-gp-specific substrate talinolol was found under co-administration of both PIs, ritonavir and H17, with highest absorption rates in the ileal and colon segment. H17 proved to be a better P-gp inhibitor than ritonavir by resulting IC50 values and also in the cellular uptake of rhodamine. Similar increases of permeabilities in ileum and colon have also been found for saquinavir as P-gp as well as MRP-substrate with differences in the jejunal uptake, which was found higher for H17. Additional MRP-inhibitory activities of H17 were proved by increasing cellular uptake rates of carboxyfluorescein in MRP-expressing cells.
  
  
  CONCLUSIONS
  The investigated PIs were characterized as effective P-gp inhibitors in the intestinal absorption of P-gp substrates. H17 showed MRP-inhibitory effects that also favor intestinal drug absorption of corresponding substrates. With respect to combined therapeutic application of PIs, compounds like H17 raise hopes for improved bioavailability of poorly absorbed compounds.
authors.affiliation: Department of Pharmaceutical Chemistry, Martin-Luther-University Halle-Wittenberg, D-06120 Halle, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Richter
authors.forename: Nóra
authors.initials: N
authors.lastname: Gyémánt
authors.forename: Joséf
authors.initials: J
authors.lastname: Molnár
authors.forename: Andreas
authors.initials: A
authors.lastname: Hilgeroth
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000378:metabolism; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects*; D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics; D000465:Algorithms; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D017320:HIV Protease Inhibitors / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007408:Intestinal Absorption; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D010477:Perfusion; D010539:Permeability; D011412:Propanolamines / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D019258:Saquinavir / Q000493:pharmacokinetics; D013601:T-Lymphocytes / Q000378:metabolism
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000319:Adrenergic beta-Antagonists; D017320:HIV Protease Inhibitors; D011412:Propanolamines; C011550:talinolol; D019258:Saquinavir