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British American Tobacco, ScitoVation, and IONTOX Present Poster On Multiple Organ Lung-Liver-PK Model at SOT 2016

55th Annual Meeting of the Society of Toxicology

Development of an In Vitro Pharmacokinetic Model to Describe Nicotine Kinetics in a MultiOrgan Culture System Abstract no. 2188.

Y. Zhao3, M. Yoon3, M. D. Gaca1, G. Phillips1, H. Clewell3, M. E. Andersen3 and J. M. McKim2. 1British American Tobacco, R&D Centre, Southampton, United Kingdom; 2IONTOX, Kalamazoo, MI and 3The Hamner Institutes for Health Sciences, Research Triangle Park, NC.

There has been a rapid growth in new in vitro methods designed to replace animal safety tests. Currently, there is a need for an in vitro integrated organ system coupled with an integrated “blood flow” that can examine systemic toxicity in humans. A well-characterized system should allow for the development of pharmacokinetic models that predict drug or chemical movement in vitro. The aim of this study was to investigate the kinetics of nicotine in a two organ system as a case study of simulating inhalation exposure in vitro and to develop a pharmacokinetic model. A dynamic multi-organ plate (DMOP) comprised of a simple, two organ compartment system containing human lung tissue (MucilAir) in one chamber and human hepatocytes (HepG2) in the other. The chambers were linked by a fluidics/dialysis network. The dialysis membrane allows for exchange of test article and metabolites while maintaining optimized media conditions. A kinetic model was developed to describe the disposition of nicotine after a single concentration (1000 µM) was applied to the apical side of the MucilAir lung. The model included diffusion apical-basolateral, movement from basolateral lung-liver, perfusion of fluid through the dialysis tubing, and nicotine in the perfusate. Nicotine in the basolateral chamber diffused into the fluidics system via dialysis and was carried to the delivery well. A static sample from the basolateral and delivery chambers was collected every hour for 6 hrs. Perfusate from the fluidics system was collected at integrated one hour time intervals for 6 hr at a flow rate of 1 µL/ min. Nicotine was first detected in the basolateral chamber at 1 hr and reached a maximum concentration (3-4 µg/mL) by 5 hr. Nicotine was first detected in the delivery chamber at approximately 3 hr and increased linearly up to 0.3 µg/mL. Nicotine in the run through perfusate was also detected at 3 hr. The current model simulated the observed concentration-time profiles of nicotine in the DMOP system. Simulation results indicated that the test compound was successfully delivered from the exposure site to the target tissue through dialysis suggesting the applicability of the DMOP for simulating systemic effects of a compound after inhalation exposure with further optimization of flow patterns in the plate.

Y Zhao, M.Yoon, M.D. Gaca, G.Phillips, H. Clewell, M.E. Andersen, J.M. McKim. Development of an In Vitro Pharmacokinetic Model to Describe Nicotine Kinetics in a MultiOrgan Culture System. In: The Toxicologist: Supplement to Toxicological Sciences, 150 (1), Society of Toxicology, 2016. Abstract no. 2188.


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