title: Toxicokinetics of α-thujone following intravenous and gavage administration of α-thujone or α- and β-thujone mixture in male and female F344/N rats and B6C3F1 mice.
abstract: Plants containing thujone have widespread use and hence have significant human exposure. α-Thujone caused seizures in rodents following gavage administration. We investigated the toxicokinetics of α-thujone in male and female F344/N rats and B6C3F1 mice following intravenous and gavage administration of α-thujone or a mixture of α- and β-thujone (which will be referred to as α,β-thujone). Absorption of α-thujone following gavage administration was rapid without any dose-, species-, sex- or test article-related effect. Absolute bioavailability of α-thujone following administration of α-thujone or α,β-thujone was generally higher in rats than in mice. In rats, females had higher bioavailability than males following administration of either test article although a sex difference was not observed in mice. Cmax and AUC∞ increased greater than proportional to the dose in female rats following administration of α-thujone and in male and female mice following administration of α,β-thujone suggesting possible saturation of elimination kinetics with increasing dose. Dose-adjusted AUC∞ for male and female rats was 5- to 15-fold and 3- to 24-fold higher than mice counterparts following administration of α-thujone and α,β-thujone, respectively (p-value<0.0001 for all comparisons). Following both intravenous and gavage administration, α-thujone was distributed to the brains of rats and mice with females, in general, having higher brain:plasma ratios than males. These data are in support of the observed toxicity of α-thujone and α,β-thujone where females were more sensitive than males of both species to α-thujone-induced neurotoxicity. In general there was no difference in toxicokinetics between test articles when normalized to α-thujone concentration.
authors.affiliation: Division of National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA. waidyanathas@niehs.nih.gov
authors.forename: Suramya
authors.initials: S
authors.lastname: Waidyanatha
authors.forename: Jerry D
authors.initials: JD
authors.lastname: Johnson
authors.forename: S Peter
authors.initials: SP
authors.lastname: Hong
authors.forename: Veronica Godfrey
authors.initials: VG
authors.lastname: Robinson
authors.forename: Seth
authors.initials: S
authors.lastname: Gibbs
authors.forename: Steven W
authors.initials: SW
authors.lastname: Graves
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Hooth
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Smith
mesh_terms: D000465:Algorithms; D000818:Animals; D019540:Area Under Curve; D000081008:Bicyclic Monoterpenes; D001682:Biological Availability; D001923:Brain Chemistry / Q000187:drug effects; D002626:Chemistry, Pharmaceutical; D003627:Data Interpretation, Statistical; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006207:Half-Life; D007275:Injections, Intravenous; D007441:Intubation, Gastrointestinal; D007536:Isomerism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D039821:Monoterpenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D010599:Pharmacokinetics; D051381:Rats; D011916:Rats, Inbred F344
chemical_list: D000081008:Bicyclic Monoterpenes; D039821:Monoterpenes; C005790:beta-thujone
keywords: Bioavailability; Gavage; Neurotoxicity; Rodents; Thujone; Toxicokinetics