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The distribution of maraviroc to the central nervous system and gut‐associated lymphoid tissue of rat
Author(s) -
Walker Donald Kim,
Bowers Sarah Jane,
Mitchell Richard,
Potchoiba Michael,
Schroeder Clinton,
Small Helen
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.661
Subject(s) - maraviroc , lymph , lymphatic system , cerebrospinal fluid , pharmacology , central nervous system , blood–brain barrier , pharmacokinetics , immunology , medicine , biology , pathology , human immunodeficiency virus (hiv)
Preclinical studies were performed to characterise the disposition of the CCR5 antagonist, maraviroc, to potential viral sanctuary sites in the central nervous system (CNS) and gut‐associated lymphoid tissue (GALT). These anatomical regions have been identified as reservoirs for HIV which may result in viral rebound on cessation or interruption of drug therapy. As maraviroc represents a novel mechanism for the treatment of HIV infection, it is important to relate the disposition to its potential pharmacological activity in these tissues. Studies were performed with labelled and unlabelled compound in rats with analysis of plasma and cerebrospinal fluid (CSF) by specific HPLC‐MS methods and analysis of tissue by whole body autoluminography. Maraviroc, which has been shown to be a substrate of the efflux transporter, P‐glycoprotein (PGP), exhibited limited penetration to the CNS with low brain tissue concentrations of radioactivity and CSF levels which were approximately 10% of the free plasma concentration. Exposure of maraviroc in GALT was relatively high with radioactivity in the GALT lymph nodes at levels approximately 7 times those in blood and also in the contents of the thoracic duct (lymph and chyle) at levels approximately equal to blood concentrations. These data suggest that HIV that may be present in CNS tissue and GALT will be exposed to maraviroc at therapeutically relevant concentrations.