title: A multisystem investigation of raltegravir association with intestinal tissue: implications for pre-exposure prophylaxis and eradication.
abstract: OBJECTIVE
  Recent clinical data have suggested high raltegravir concentrations in gut tissue after oral administration, with implications for treatment and prevention. We have used in silico, in vitro, ex vivo and in vivo models to further investigate the accumulation of raltegravir in gut tissue.
  
  
  METHODS
  Affinity of raltegravir for gut tissue was assessed in silico (Poulin-Theil method), in vitro (Caco-2 accumulation) and ex vivo (rat intestine) and compared with the lipophilic drug lopinavir. Finally, raltegravir concentrations in plasma, gut contents, small intestine and large intestine were determined after oral dosing to Wistar rats 1 and 4 h post-dose. Samples were analysed using LC-MS/MS and scintillation counting.
  
  
  RESULTS
  Gut tissue accumulation of raltegravir was less than for lopinavir in silico, in vitro and ex vivo (P < 0.05). After oral administration to rats, raltegravir concentrations 4 h post-dose were lower in plasma (0.05 μM) compared with small intestine (0.47 μM, P = 0.06) and large intestine (1.36 μM, P < 0.05). However, raltegravir concentrations in the contents of both small intestine (4.0 μM) and large intestine (40.6 μM) were also high.
  
  
  CONCLUSIONS
  In silico, in vitro and ex vivo data suggest low raltegravir accumulation in intestinal tissue. In contrast, in vivo animal data suggest raltegravir concentrates in intestinal tissue even when plasma concentrations are minimal. However, high raltegravir concentrations in gut contents are the likely driving factor behind this observation, rather than blood-to-tissue drug distribution. The methods described can be combined with clinical investigations to provide a complete strategy for selection of drugs with high gut accumulation.
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK darren.moss@liverpool.ac.uk.
authors.forename: Darren M
authors.initials: DM
authors.lastname: Moss
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Curley
authors.affiliation: Department of Parasitology, Liverpool School of Tropical Medicine, Liverpool, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Shone
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Marco
authors.initials: M
authors.lastname: Siccardi
authors.affiliation: Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Owen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002853:Chromatography, Liquid; D015658:HIV Infections / Q000188:drug therapy* / Q000517:prevention & control*; D007422:Intestines / Q000737:chemistry*; D008297:Male; D065129:Pre-Exposure Prophylaxis; D011760:Pyrrolidinones / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000068898:Raltegravir Potassium; D017208:Rats, Wistar; D053719:Tandem Mass Spectrometry
chemical_list: D019380:Anti-HIV Agents; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium
keywords: HIV; PreP; tissue drug concentrations