{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T11:20:18Z","timestamp":1789039218956,"version":"build-2803163510"},"reference-count":50,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T00:00:00Z","timestamp":1595980800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institutes of Health National Cancer Institute","award":["R44CA210763"],"award-info":[{"award-number":["R44CA210763"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2020,12]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Cachexia is a debilitating, life\u2010threatening condition whose pathology includes reduced food intake accompanied by hypermetabolism, leading to a catabolic state. The hypothalamic melanocortin system is a critical regulator of metabolic rate with effects being mediated through the melanocortin\u20104 receptor (MC4R). MC4R activation is also critical to the initiation and maintenance of cachexia. A major problem in the design of anti\u2010cachexia drugs has been the need to cross the blood\u2013brain barrier to access the metabolic rate\u2010controlling centres in the hypothalamus. The overwhelming majority of anti\u2010cachexia drugs are only effective when administered intracerebroventricularly. TCMCB07 is a cyclic nonapeptide peptide MC4R antagonist with parenteral anti\u2010cachexia activity in both small and large animal models. This suggests it can cross the blood\u2013brain barrier. The aim of this study was to examine potential transport mechanisms of TCMCB07 furthering its preclinical development for subsequent studies in humans.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p><jats:italic>In vitro<\/jats:italic> studies were performed in transporter\u2010transfected cells to study whether or not TCMCB07 was an inhibitor as well as substrate for OATP1A2, OATP1B1, OATP1B3, OATP2B1, OCT2, OAT1, OAT3, MATE1, MATE2\u2010K, P\u2010gp (MDR1), and BCRP. <jats:italic>In vivo<\/jats:italic> mass balance studies were also performed in mice to evaluate the absorption and disposition of TCMCB07 after oral and intravenous bolus administrations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>TCMCB07 inhibited the uptake of prototypical substrates in cells transfected with OATP1A2 (IC<jats:sub>50<\/jats:sub> 24.0\u00a0\u03bcM), OATP1B1 (IC<jats:sub>50<\/jats:sub> 6.8\u00a0\u03bcM), OATP1B3 (IC<jats:sub>50<\/jats:sub> 307\u00a0\u03bcM), OATP2B1 (IC<jats:sub>50<\/jats:sub> 524\u00a0\u03bcM), OCT2 (IC<jats:sub>50<\/jats:sub> 1,169\u00a0\u03bcM), MATE1 (IC<jats:sub>50<\/jats:sub> 8.7\u00a0\u03bcM), and MATE2\u2010K (IC<jats:sub>50<\/jats:sub> 20.7\u00a0\u03bcM) but not in cells transfected with OAT1 and OAT3. TCMCB07 did not affect the P\u2010gp (MDR1)\u2010mediated and BCRP\u2010mediated permeability of prototypical substrates in transfected cells. Importantly, direct evidence was shown for the uptake of TCMCB07 in OATP1A2\u2010transfected cells (i.e. <jats:italic>V<\/jats:italic><jats:sub>max<\/jats:sub> 236\u00a0pmol\/mg, <jats:italic>K<\/jats:italic><jats:sub><jats:italic>m<\/jats:italic><\/jats:sub> 58.4\u00a0\u03bcM, and <jats:italic>K<\/jats:italic><jats:sub><jats:italic>d<\/jats:italic><\/jats:sub> 0.39\u00a0\u03bcL\/mg), demonstrating that the nonapeptide was a substrate for this transporter. Mass balance studies demonstrated that 24.2% of TCMCB07 was absorbed orally <jats:italic>in vivo<\/jats:italic> (<jats:italic>P<\/jats:italic>\u00a0=\u00a00.0033) and excreted primarily in the bile after both oral and intravenous administrations.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>OATP1A2 is the transporter responsible for the oral absorption of TCMCB07 in the intestine and for its pharmacologic response in the brain.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12602","type":"journal-article","created":{"date-parts":[[2020,7,29]],"date-time":"2020-07-29T07:16:53Z","timestamp":1596007013000},"page":"1677-1687","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Characterization of the cellular transport mechanisms for the anti\u2010cachexia candidate compound TCMCB07"],"prefix":"10.1002","volume":"11","author":[{"given":"Yongjun","family":"Hu","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, College of Pharmacy University of Michigan  Ann Arbor MI USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth A.","family":"Gruber","sequence":"additional","affiliation":[{"name":"Tensive Controls, Inc.  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