Pharmacokinetics of 1,8-cineole, a dietary toxin, in the brushtail possum (Trichosurus vulpecula): Significance for feeding

Abstract

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.

The dilemma of foraging herbivores: dealing with food and fear

“…Specialists can cope with higher toxin concentrations than generalists by reducing toxin absorption (Sorensen et al 2004) or by using more efficient or less expensive metabolic pathways (Boyle et al 1999;Shipley et al 2012). These processes delay the physiological feedback affecting intake, which is instigated by the plasma concentration of the toxin or its metabolites (McLean et al 2007), the emetic system (Provenza et al 1994;Lawler et al 1998), dose-dependent inhibition of cellular function (Forbey et al 2011) or possibly acidosis (Foley 1992).…”

A Pharm-Ecological Perspective of Terrestrial and Aquatic Plant-Herbivore Interactions

“…The mechanisms of absorption of PSMs and the resultant kinetics (i.e. time course) of secondary metabolites are known in some vertebrate (Boyle et al, 2005;Dziba et al, 2006;Mclean et al, 2007) and invertebrate herbivores (Zangerl et al 2012). However, detailed pharmacokinetic studies where the concentration-time profile is linked to a specific mechanisms (e.g.…”

“…Only a single study has examined the effect of blood concentration of PSMs on intake in a wild mammal (Mclean et al, 2007), which may be critical to predicting foraging phenotypes in nature. The link between intake, blood (or other body compartment) concentration, and more specifically, distribution to specific tissues deserves attention if we want to know the mechanism of action of PSMs.…”

The effect of plant secondary metabolites on the interplay between the internal and external environments of marsupial folivores

“…have shown that limitations to detoxification can in fact act as signals to stop feeding. For example, McLean et al (2007) characterised the pharmacokinetics of 1,8-cineole in common brushtail possums and found that they ate until the cineole consumed saturated the pre-systemic metabolism, which led to a rapid rise in the concentration of cineole in the blood and a cessation of the meal. Marsh et al (2005) showed that when additional glycine was provided orally to common brushtail possums fed benzoic acid, they were able to increase the rate of conjugation and consequential excretion of urinary benzoyl glycine (hippuric acid) and so eat more than control animals.…”