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A multisystem investigation of raltegravir association with intestinal tissue: implications for pre-exposure prophylaxis and eradication

A multisystem investigation of raltegravir association with intestinal tissue: implications for pre-exposure prophylaxis and eradication Thumbnail


Abstract

Objectives
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.

Acceptance Date Jul 18, 2014
Publication Date Aug 11, 2014
Journal Journal of Antimicrobial Chemotherapy
Print ISSN 0305-7453
Publisher Oxford University Press
Pages 3275-3281
DOI https://doi.org/10.1093/jac/dku312
Keywords PreP; HIV; tissue drug concentrations
Publisher URL https://doi.org/10.1093/jac/dku312

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