McLean S, Boyle R R, Brandon S, Davies N W, Sorensen J S
School of Pharmacy, University of Tasmania, Hobart, Tasmania, Australia.
Xenobiotica. 2007 Sep;37(9):903-22. doi: 10.1080/00498250701570277.
1,8-Cineole (cineole) is a Eucalyptus leaf toxin that defends against predation by herbivores such as the brushtail possum (Trichosurus vulpecula). The aim of the current study was to characterize the pharmacokinetics of cineole in the possum to improve understanding about how possums can avoid cineole toxicity when eating a Eucalyptus diet. Nine male possums were trapped in the wild and acclimated to captivity; a subcutaneous port was then implanted for venous blood sampling. Cineole was administered intravenously (10 and 15 mg kg(-1)) via a lateral tail vein and orally (30, 100 and 300 mg kg(-1)) by gavage, and blood concentrations of cineole and its metabolites were determined by gas chromatography. Cineole had a large terminal volume of distribution (V(z) = 27 l kg(-1)) and a high clearance (43 ml min(-1) kg(-1)), equal to hepatic blood flow. The terminal half-life was approximately 7 h. Oral bioavailability was low (F = 0.05) after low doses, but increased tenfold with dose, probably due to saturable first-pass metabolism. These findings indicate that when possums feed on a cineole diet, they eat until the cineole consumed is sufficient to saturate pre-systemic metabolism, leading to a rapid rise in bioavailability and cineole blood levels, and a cessation of the feeding bout. This is the first report on the pharmacokinetics of a dietary toxin in a wild herbivore, and provides insights into the interactions between the blood concentration of a plant secondary metabolite and the browsing behaviour of a herbivore.
1,8-桉叶素（桉叶油素）是一种桉树叶毒素，可抵御诸如帚尾袋貂（Trichosurus vulpecula）等食草动物的捕食。本研究的目的是表征桉叶油素在袋貂体内的药代动力学，以增进对袋貂在食用桉树叶饮食时如何避免桉叶油素毒性的理解。9只雄性袋貂在野外捕获并适应圈养环境；随后植入皮下端口用于采集静脉血样。桉叶油素通过外侧尾静脉静脉注射（10和15 mg kg⁻¹），并通过灌胃口服（30、100和300 mg kg⁻¹），桉叶油素及其代谢物的血药浓度通过气相色谱法测定。桉叶油素具有较大的终末分布容积（V(z) = 27 l kg⁻¹）和较高的清除率（43 ml min⁻¹ kg⁻¹），与肝血流量相当。终末半衰期约为7小时。低剂量时口服生物利用度较低（F = 0.05），但随剂量增加十倍，可能是由于首过代谢饱和所致。这些发现表明，当袋貂以含桉叶油素的饮食为食时，它们会一直进食，直到摄入的桉叶油素足以使首过代谢饱和，从而导致生物利用度和桉叶油素血药浓度迅速升高，并停止进食。这是关于野生食草动物饮食毒素药代动力学的首次报告，并为植物次生代谢物血药浓度与食草动物采食行为之间的相互作用提供了见解。
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