{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T05:37:39Z","timestamp":1777354659236,"version":"3.51.4"},"reference-count":34,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2018,5,22]],"date-time":"2018-05-22T00:00:00Z","timestamp":1526947200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Queen Elizabeth Hospital Research Foundation and Adelaide University"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Pharmacology Res &amp; Perspec"],"published-print":{"date-parts":[[2018,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Perhexiline, a chiral drug, is a potent antiischemic agent whose clinical utility is limited by hepatic and neural toxicities. It inhibits mitochondrial carnitine palmitoyltransferase\u20101, however, excessive inhibition predisposes toward tissue steatosis. This pilot study investigated the distribution of the two enantiomers and their toxicological potential. Dark Agouti rats (n\u00a0=\u00a04 per group) were administered vehicle or 200\u00a0mg\/kg daily of racemic, (+)\u2212 or (\u2212)\u2010perhexiline maleate orally for 8\u00a0weeks. Plasma biochemical liver function tests and Von Frey assessments of peripheral neural function were performed. Hepatic and neuronal histology, including lipid and glycogen content, was assessed using electron microscopy. Concentrations of the perhexiline enantiomers and metabolites were quantified in plasma, liver and heart. Plasma perhexiline concentrations following administration of racemate, (+)\u2212 or (\u2010)\u2010enantiomer were within the mid\u2010upper clinical therapeutic range. There was extensive uptake of both enantiomers into liver and heart, with 2.5\u2010 to 4.5\u2010fold greater net uptake of (+)\u2010 compared to (\u2212)\u2010perhexiline (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.05) when administered as pure enantiomers, but not when administered as racemate. There was no biochemical or gross histological evidence of hepatotoxicity. However, livers of animals administered (+)\u2010perhexiline had higher lipid (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.01) and lower glycogen (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.05) content, compared to those administered (\u2212)\u2010perhexiline. Animals administered racemic perhexiline had reduced peripheral neural function (<jats:italic>P<\/jats:italic>\u00a0&lt;\u00a0.05) compared to controls or animals administered (\u2212)\u2010perhexiline. For the same plasma concentrations, differences in tissue distribution may contribute to disparities in the effects of (+)\u2010 and (\u2212)\u2010perhexiline on hepatic histology and neural function.<\/jats:p>","DOI":"10.1002\/prp2.406","type":"journal-article","created":{"date-parts":[[2018,5,31]],"date-time":"2018-05-31T19:34:45Z","timestamp":1527795285000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Enantioselectivity in the tissue distribution of perhexiline contributes to different effects on hepatic histology and peripheral neural function in rats"],"prefix":"10.1002","volume":"6","author":[{"given":"Giovanni","family":"Licari","sequence":"first","affiliation":[{"name":"Discipline of Pharmacology University of Adelaide Adelaide South Australia Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert W.","family":"Milne","sequence":"additional","affiliation":[{"name":"School of 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