Exhaled breath analysis presents a promising approach for drug monitoring. While the range of drugs known to undergo pulmonary exhalation remains limited, innovative experimental models are needed to explore this field. This study aimed to develop an ex-vivo platform as a general experimental setup for studying volatile and semi-volatile compounds in exhaled breath, using propofol as a pragmatic validation compound because it can be reliably detected both in exhaled air and in blood under our experimental conditions. A porcine lung model was created using lungs from a commercial slaughter. Each experiment was performed with a single isolated lung in an individual setup. The lungs were perfused and ventilated. Propofol exhalation was validated under various conditions (boluses, infusion rates, blood flow, and ventilation) using a propofol calibrated multi-capillary column-ion mobility spectrometer (MCC-IMS). Blood gas analysis and plasma concentration samples were collected every 20 min to continuously monitor propofol plasma levels, pulmonary respiration, and metabolism. We established a functional ex-vivo platform using nine commercially slaughtered porcine lungs, enabling extended measurements for up to 13 h. Hematocrit was set to 35% and hemoglobin to approximately 12 g dl−1, with glucose supplementation of 921 mg h−1. Lactate increased by 308% over the perfusion period. The lungs were ventilated in volume-controlled mode (Vt 700 ml, RR 14 min−1, PEEP 8 mbar, I:E 1:1) and perfused at a standard blood flow of 1.0 l min−1, and mean pH was 7.31 over the perfusion period. Exhaled Propofol was detected on average 19 min after the first administration using MCC-IMS. Changes in blood flow and minute volume were accompanied by corresponding changes in the time course and magnitude of exhaled propofol. This ex-vivo model of perfused and ventilated porcine lungs provides a controlled setting to study the appearance of intravenously administered drugs in exhaled air under defined ventilation and perfusion conditions. The platform enabled prolonged measurements and detection of exhaled propofol signals and may support future screening of candidate drugs for breath-based drug monitoring pending validation across additional compounds and conditions.