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.

Key Words::

• 1,8-Cineole
• monoterpene pharmacokinetics
• monoterpene metabolism
• brushtail possum (Trichosurus vulpecula)
• herbivory

Acknowledgements

The authors would like to thank the staff at the Central Animal House, University of Tasmania, for their care and assistance with possum husbandry, particularly Barbara Arnts for preparing the diet and her care in the maintenance of vascular access ports. They are very grateful for the surgical expertise and enthusiasm of Dr Eileen Wronski and Dr Rupert Woods who were responsible for the implantation of vascular access ports in possums. Dr David Shackleford (Victorian College of Pharmacy) kindly advised on the formulation of the intravenous dose. They also appreciate the assistance of Mel Lambourne with animal experiments; Dr Alison Featherstone for blood metabolite analyses; and Dr Omar Hasan for his prompt and expert assistance in the maintenance of laboratory equipment. This project was supported by a grant from The Australian Research Council. Jennifer Sorensen was a recipient of a National Science Foundation (USA) International Research Fellowship INT-0301898.