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Using mice as a model organism, we performed a multiscale, quantitative analysis to reveal the sites of clofazimine bioaccumulation during chronic, long-term exposure. Remarkably, between 3 and 8 weeks of dietary administration, clofazimine massively redistributed from adipose tissue to liver and spleen. During this time, clofazimine concentration in fat and serum significantly decreased, while the mass of clofazimine in spleen and liver increased by &gt;10-fold. These changes were paralleled by the accumulation of clofazimine in the resident macrophages of the lymphatic organs, with as much as 90% of the clofazimine mass in spleen sequestered in intracellular crystal-like drug inclusions (CLDIs). The amount of clofazimine associated with CLDIs of liver and spleen macrophages disproportionately increased and ultimately accounted for a major fraction of the total clofazimine in the host. After treatment was discontinued, clofazimine was retained in spleen while its concentrations decreased in blood and other organs. Immunologically, clofazimine bioaccumulation induced a local, monocyte-specific upregulation of various chemokines and receptors. However, interleukin-1 receptor antagonist was also upregulated, and the acute-phase response pathways and oxidant capacity decreased or remained unchanged, marking a concomitant activation of an anti-inflammatory response. These experiments indicate an inducible, immune system-dependent, xenobiotic sequestration response affecting the atypical pharmacokinetics of a small molecule chemotherapeutic agent.<\/jats:p>","DOI":"10.1128\/aac.01731-12","type":"journal-article","created":{"date-parts":[[2012,12,22]],"date-time":"2012-12-22T07:48:00Z","timestamp":1356162480000},"page":"1218-1230","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":74,"title":["Multiscale Distribution and Bioaccumulation Analysis of Clofazimine Reveals a Massive Immune System-Mediated Xenobiotic Sequestration Response"],"prefix":"10.1128","volume":"57","author":[{"given":"Jason","family":"Baik","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen A.","family":"Stringer","sequence":"additional","affiliation":[{"name":"Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerta","family":"Mane","sequence":"additional","affiliation":[{"name":"Department of Clinical, Social, and Administrative Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gus R.","family":"Rosania","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, University of Michigan College of Pharmacy, Ann Arbor, Michigan, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.1974.23.1110"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1043-6618(02)00086-5"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1093\/jac\/dkr444"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.3109\/03602539508994208"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.1974.23.1116"},{"key":"e_1_3_3_7_2","first-page":"472","article-title":"Tissue distribution and deposition of clofazimine in mice following oral administration with or without isoniazid","volume":"57","author":"Venkatesan K","year":"2007","unstructured":"VenkatesanK DeoN GuptaUD. 2007. 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