Absolute oral bioavailability, quantitative toxicokinetics and metabolite profiling of alternariol and alternariol monomethyl ether in pigs

Abstract

The mycotoxins alternariol (AOH) and alternariol monomethyl ether (AME), produced by Alternaria spp . , are common contaminants of food and feed and are a potential threat to animal and human health. To date, the most prominent data gaps for their comprehensive risk assessment concern information on their in vivo absorption, distribution, metabolism and excretion (ADME) and toxicokinetic behavior. The aim of this study was to determine the absolute oral bioavailability, quantitative toxicokinetic characteristics and biotransformation of AOH and AME in vivo in pigs, using crossover trials with intravenous and oral administration of a single dose of both mycotoxins at 2 mg/kg b.w. Plasma profiles of the mycotoxins and phase I and II metabolites were studied in the vena jugularis using UPLC-MS/MS and LC-HRMS methods. Furthermore, plasma from the vena portae was analyzed to study presystemic biotransformation. Urine was collected to determine the urinary excretion and metabolite profiles. Results reveal a low absolute oral bioavailability of AOH (15%) and AME (9%), caused by a low absorption and/or extensive first-pass biotransformation in the liver to mainly phase II, and to a lesser extent phase I metabolites. Quantitative toxicokinetic modeling of the IV data showed a high total body clearance for both AOH and AME (12.9 and 16.8 L/(h*kg b.w.), respectively), a high volume of distribution (4.97 and 5.15 L/kg b.w., respectively) and a short elimination half-life of 0.16 and 0.21 h, respectively. These findings may contribute to the risk assessment of AOH and AME and to the development of candidate biomarkers of exposure in biomonitoring studies since pigs are considered a suitable animal model to extrapolate to humans.

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