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

Moss, D. M., Curley, P., Shone, Alison, 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, Vol 69, Issue 12, pp. 3275-3281.

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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.

Item Type: Article
Subjects: WC Communicable Diseases > Virus Diseases > Acquired Immunodeficiency Syndrome. HIV Infections > WC 503 Acquired immunodeficiency syndrome. HIV infections
WC Communicable Diseases > Virus Diseases > Acquired Immunodeficiency Syndrome. HIV Infections > WC 503.2 Therapy
WC Communicable Diseases > Virus Diseases > Acquired Immunodeficiency Syndrome. HIV Infections > WC 503.6 Prevention and control
Faculty: Department: Biological Sciences > Department of Tropical Disease Biology
Digital Object Identifer (DOI): https://doi.org/10.1093/jac/dku312
Depositing User: Lynn Roberts-Maloney
Date Deposited: 07 Jan 2015 11:17
Last Modified: 06 Feb 2018 13:08
URI: https://archive.lstmed.ac.uk/id/eprint/4721

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