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To better understand the pharmacology of lysosomal SCFA donors, we investigated the distribution and metabolism of propionate and butyrate donors. Each analog (<jats:bold>1\u2009a<\/jats:bold> and <jats:bold>2\u2009a<\/jats:bold>) can donate three SCFA equivalents via ester hydrolysis through six intermediate metabolites. The compounds are stabilized by low pH, and stability in cells is usually higher than in medium, but is cell\u2010type specific. Butyrate derivatives were found to be more stable than propionates. Tri\u2010esters were more stable than di\u2010 or mono\u2010esters. The donors were surprisingly stable in\u2005vivo, and hydrolysis of each position was organ specific. Jejunum and liver caused rapid loss of 4\u2019\u2019 esters. The gut metabolite pattern by i.\u2009v. differed from that of p.o. application, suggesting luminal and apical enzyme effects in the gut epithelium. Central organs could de\u2010esterify the 11\u2010position. Levels in lung relative to other organs were higher by p.o. than via i.\u2009v., suggesting that delivery route can influence the observed pharmacology and that gut metabolites distribute differently. The donors were largely eliminated by 24\u2005h, following near linear decline in organs. The observed levels and distribution were found to be consistent with pharmacodynamic effects, particularly in the gut.<\/jats:p>","DOI":"10.1002\/cmdc.202100139","type":"journal-article","created":{"date-parts":[[2021,3,31]],"date-time":"2021-03-31T04:29:00Z","timestamp":1617164940000},"page":"2254-2269","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Synthesis, Characterization, and in\u2005vivo Distribution of Intracellular Delivered Macrolide Short\u2010Chain Fatty Acid Derivatives"],"prefix":"10.1002","volume":"16","author":[{"given":"Simon","family":"Stra\u00df","sequence":"first","affiliation":[{"name":"Pharmaceutical Chemistry Institute for Pharmaceutical Sciences Eberhard-Karls-Universit\u00e4t T\u00fcbingen  Auf der Morgenstelle 8 72076 T\u00fcbingen Germany"},{"name":"Synovo GmbH  Paul-Ehrlich Stra\u00dfe 15 72076 T\u00fcbingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Schwamborn","sequence":"additional","affiliation":[{"name":"Synovo GmbH  Paul-Ehrlich Stra\u00dfe 15 72076 T\u00fcbingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manuel","family":"Keppler","sequence":"additional","affiliation":[{"name":"Synovo GmbH  Paul-Ehrlich Stra\u00dfe 15 72076 T\u00fcbingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natascha","family":"Cloos","sequence":"additional","affiliation":[{"name":"Synovo GmbH  Paul-Ehrlich Stra\u00dfe 15 72076 T\u00fcbingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jamil","family":"Guezguez","sequence":"additional","affiliation":[{"name":"Synovo GmbH  Paul-Ehrlich Stra\u00dfe 15 72076 T\u00fcbingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan\u2010Hinrich","family":"Guse","sequence":"additional","affiliation":[{"name":"Synovo GmbH  Paul-Ehrlich Stra\u00dfe 15 72076 T\u00fcbingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4311-5441","authenticated-orcid":false,"given":"Michael","family":"Burnet","sequence":"additional","affiliation":[{"name":"Synovo GmbH  Paul-Ehrlich Stra\u00dfe 15 72076 T\u00fcbingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stefan","family":"Laufer","sequence":"additional","affiliation":[{"name":"Pharmaceutical Chemistry Institute for Pharmaceutical Sciences Eberhard-Karls-Universit\u00e4t T\u00fcbingen  Auf der Morgenstelle 8 72076 T\u00fcbingen Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,5,11]]},"reference":[{"key":"e_1_2_6_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.trsl.2012.10.007"},{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-019-0157-3"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2018.05.003"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2012.00111"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2036.2007.03562.x"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2013.12.007"},{"key":"e_1_2_6_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11883-013-0325-9"},{"key":"e_1_2_6_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1215927110"},{"journal-title":"Curr. 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