Moss, DM, Curley, P, Shone, A, Siccardi, M and Owen, A (2014) A multisystem investigation of raltegravir association with intestinal tissue: implications for pre-exposure prophylaxis and eradication. Journal of Antimicrobial Chemotherapy, 69 (12). pp. 3275-3281. ISSN 0305-7453

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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.

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.

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.

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.

Item Type: Article
Additional Information: his is a pre-copyedited, author-produced version of an article accepted for publication in Journal of Antimicrobial Chemotherapy following peer review. The version of record is available online at:
Uncontrolled Keywords: PreP; HIV; tissue drug concentrations
Subjects: R Medicine > RM Therapeutics. Pharmacology
Divisions: Faculty of Medicine and Health Sciences > Institute for Applied Clinical Sciences
Depositing User: Symplectic
Date Deposited: 22 Feb 2017 11:53
Last Modified: 20 May 2019 07:55

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