{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T11:01:33Z","timestamp":1782730893285,"version":"3.54.5"},"reference-count":62,"publisher":"American Association for Laboratory Animal Science","issue":"5","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,9]]},"abstract":"<jats:p>Pharmaceutical-grade medium-chain triglycerides (MCTs) are common excipients for in vivo pharmacological studies in laboratory animals and as an experimental therapeutic in certain metabolic and neurologic disorders. In this study, we examined the tolerability of repeated administration of a pharmaceutical-grade formulation of 3 MCTs\u2014caprylic, capric, and lauric acid\u2014in mice via the oral and intraperitoneal routes. We administered either 8 or 4 \u00b5L of 100% MCTs or saline\/gram of body weight (\u223c7.56 or 3.78 g\/kg, respectively) twice daily for 7 d. During administration, and for 7 d after, we monitored weight change and clinical presentation. On day 14, or upon meeting euthanasia criteria, animals were sacrificed for gross necropsy, histology, and CBC. We observed significant weight loss, clinical decline, and 100% mortality in animals receiving 8 \u00b5L\/g MCTs via the intraperitoneal route of administration. Gross necropsy revealed serosanguinous fluid in the thoracic cavity, dark red mottled lungs, and adhesions in the abdominal cavity. Histology confirmed inflammation of the lungs, mediastinum, and peritoneum. Mild pathology and initial weight loss (through day 3) were also present in mice receiving 4 \u00b5L\/g MCTs IP. However, these animals regained weight by day 7 and exhibited no clinical decline or mortality. These adverse effects were not seen in animals receiving either 8 \u00b5L\/g MCTs PO or 8 \u00b5L\/g saline IP. These findings suggest that repeated intraperitoneal administration of MCTs may cause dose-dependent toxicity and mortality at high doses, but it confers no adverse effects when administered via the oral route.<\/jats:p>","DOI":"10.30802\/aalas-jaalas-25-032","type":"journal-article","created":{"date-parts":[[2025,6,18]],"date-time":"2025-06-18T20:01:39Z","timestamp":1750276899000},"page":"812-822","source":"Crossref","is-referenced-by-count":1,"title":["Repeated Administration of Pharmaceutical-Grade Medium-Chain Triglycerides, a Common Pharmacologic Excipient, Confers Dose-Dependent Toxicity by the Intraperitoneal but Not Oral Route in Mice"],"prefix":"10.30802","volume":"64","author":[{"given":"Mitzi","family":"Adler-Wachter","sequence":"first","affiliation":[{"name":"Department of Neurology, University of Washington, School of Medicine, Seattle, Washington;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia Y","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, University of Washington, School of Medicine, Seattle, Washington; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan N","family":"Schweitzer","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Washington, School of Medicine, Seattle, Washington;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley","family":"McDonough","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Washington, School of Medicine, Seattle, Washington;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa","family":"Barker-Haliski","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, University of Washington, Seattle, Washington"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica M","family":"Snyder","sequence":"additional","affiliation":[{"name":"Department of Comparative Medicine, University of Washington, School of Medicine, Seattle, Washington; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan R","family":"Weinstein","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of Washington, School of Medicine, Seattle, Washington;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"12258","reference":[{"key":"bib1","series-title":"Characterization and Biology of Nanomaterials for Drug Delivery.","first-page":"137","article-title":"Nanolipid materials for drug delivery systems: a comprehensive review","author":"Singh Negi J","year":"2019","unstructured":"Singh Negi J. Nanolipid materials for drug delivery systems: a comprehensive review. In: SS Mohapatra, S Ranjan, N Dasgupta, RK Mishra, S Thomas, eds. Characterization and Biology of Nanomaterials for Drug Delivery. Elsevier; 2019:137\u2013163. https:\/\/doi.org\/10.1016\/C2017-0-00272-0."},{"issue":"10","key":"bib2","series-title":"J Appl Toxicol.","first-page":"1293","article-title":"Nonclinical safety and pharmacokinetics of Miglyol 812: a medium chain triglyceride in exenatide once weekly suspension","volume":"38","author":"Buss N","year":"2018","unstructured":"Buss N, Ryan P, Baughman T, et al. Nonclinical safety and pharmacokinetics of Miglyol 812: a medium chain triglyceride in exenatide once weekly suspension. 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Drug Chem Toxicol. 2005;28(4):423\u2013432."},{"issue":"1","key":"bib5","series-title":"J Appl Toxicol.","first-page":"140","article-title":"Safety data on 19 vehicles for use in 1 month oral rodent pre-clinical studies: administration of hydroxypropyl-ss-cyclodextrin causes renal toxicity","volume":"36","author":"Healing G","year":"2016","unstructured":"Healing G, Sulemann T, Cotton P, et al. Safety data on 19 vehicles for use in 1 month oral rodent pre-clinical studies: administration of hydroxypropyl-ss-cyclodextrin causes renal toxicity. J Appl Toxicol. 2016;36(1):140\u2013150."},{"issue":"2","key":"bib6","series-title":"Int J Toxicol.","first-page":"95","article-title":"Tolerable levels of nonclinical vehicles and formulations used in studies by multiple routes in multiple species with notes on methods to improve utility","volume":"35","author":"Gad SC","year":"2016","unstructured":"Gad SC, Spainhour CB, Shoemake C, et al. 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The oral absorption of phospholipid prodrugs: In vivo and in vitro mechanistic investigation of trafficking of a lecithin-valproic acid conjugate following oral administration. J Control Release. 2008;126(1):1\u20139."},{"issue":"10\u201311","key":"bib25","series-title":"Adv Drug Deliv Rev.","first-page":"923","article-title":"Intestinal lymphatic transport for drug delivery","volume":"63","author":"Y\u00e1\u00f1ez JA","year":"2011","unstructured":"Y\u00e1\u00f1ez JA, Wang SW, Knemeyer IW, Wirth MA, Alton KB. Intestinal lymphatic transport for drug delivery. Adv Drug Deliv Rev. 2011;63(10\u201311):923\u2013942."},{"issue":"1","key":"bib26","series-title":"Pharm Res.","first-page":"12","article-title":"Intraperitoneal route of drug administration: Should it be used in experimental animal studies?","volume":"37","author":"Al Shoyaib A","year":"2020","unstructured":"Al Shoyaib A, Archie SR, Karamyan VT. Intraperitoneal route of drug administration: Should it be used in experimental animal studies? Pharm Res. 2020;37(1):12."},{"issue":"1","key":"bib27","series-title":"J Pharm Pharmacol.","first-page":"47","article-title":"Oral, intraperitoneal and intravenous pharmacokinetics of deramciclane and its N-desmethyl metabolite in the rat","volume":"52","author":"Nemes KB","year":"2000","unstructured":"Nemes KB, Abermann M, Bojti E, Gr\u00e9zal G, Al-Behaisi S, Klebovich I. Oral, intraperitoneal and intravenous pharmacokinetics of deramciclane and its N-desmethyl metabolite in the rat. J Pharm Pharmacol. 2000;52(1):47\u201351."},{"issue":"12","key":"bib28","series-title":"Expert Opin Drug Metab Toxicol.","first-page":"1635","article-title":"Vehicle selection for nonclinical oral safety studies","volume":"9","author":"Thackaberry EA","year":"2013","unstructured":"Thackaberry EA. Vehicle selection for nonclinical oral safety studies. 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