Preclinical assessment of the distribution of maraviroc to potential human immunodeficiency virus (HIV) sanctuary sites in the central nervous system (CNS) and gut-associated lymphoid tissue (GALT).
1. Growing knowledge of the pathogenesis of human immunodeficiency virus (HIV)-1 infection has led to the identification of potential virus sanctuary sites within the central nervous system and gut-associated lymphoid tissue. 2. Maraviroc is a novel CCR5 antagonist for the treatment of HIV-1 infection. Disposition studies have been performed within the preclinical testing of maraviroc to determine its distribution to these anatomical sites. 3. Maraviroc, which is a substrate of the efflux transporter P-glycoprotein, shows limited distribution to the central nervous system as evidenced by cerebrospinal fluid concentrations that were 10% of the free plasma concentration following intravenous infusion to rats. Tissue distribution studies also indicated limited distribution of radioactivity into brain tissue of rats. 4. Radioactivity in gut-associated lymphoid tissue lymph nodes exceeded the concentrations in blood and concentrations in the contents of thoracic ducts of the lymphatic system were similar to blood levels following intravenous administration to rats.
Pharmacokinetics, Dynamics and Metabolism, Pfizer Global Research and Development, Sandwich, UK. don.walker@pfizer.com
D K
DK
Walker
S J
SJ
Bowers
R J
RJ
Mitchell
M J
MJ
Potchoiba
C M
CM
Schroeder
H F
HF
Small
D000818:Animals; D001921:Brain / Q000378:metabolism*; D003510:Cyclohexanes / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004353:Drug Evaluation, Preclinical; D005240:Feasibility Studies; D006678:HIV / Q000187:drug effects; D023581:HIV Fusion Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008221:Lymphoid Tissue / Q000378:metabolism*; D008297:Male; D000077592:Maraviroc; D051381:Rats; D014018:Tissue Distribution; D014230:Triazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*
D003510:Cyclohexanes; D023581:HIV Fusion Inhibitors; D014230:Triazoles; D000077592:Maraviroc