Action by the lungs on circulating xenobiotic agents, with a case study of physiologically based pharmacokinetic modeling of benzo(a)pyrene disposition

Abstract

The lungs contain enzyme systems that metabolize xenobiotic agents, and the structure and position in the circulation render this organ potentially important in the metabolic removal of substances from the blood. Pulmonary enzyme systems that oxidize xenobiotic agents include cytochrome P450- or flavin-containing monooxygenases. In addition, the lungs accumulate certain agents, notably basic amines, without substantially metabolizing them. Benzo(a)pyrene (B(a)P) is one example of a xenobiotic agents that is eliminated from the circulation largely by oxidative metabolism. We have described the metabolic elimination of B(a)P using a physiologically based pharmacokinetic model applied retrospectively to existing data sets of B(a)P metabolism and disposition in rats. The result suggests that the lungs may, under certain conditions, contribute significantly to xenobiotic disposition and that this contribution is greater than that predicted by the activity of dispositional enzyme in this organ. Thus, the lungs may play a significant role in the metabolic elimination of some xenobiotic agents under certain circumstances.