The dilution of an intravenous bolus dose of [¹³C]bicarbonate is used as an estimate for the metabolic rate under certain conditions. It is a consistent finding in all studies that the total amount of intravenous [¹³C]bicarbonate cannot be recovered as breath ¹³CO₂. In this study, we used a breath-by-breath analysis of ¹³CO₂ to depict the washout of ¹³CO₂ at a high temporal resolution to analyze the extent to which a probable first-pass effect is responsible for the reduced recovery. Eight healthy men were tested at seated rest and with bicycle exercise at a constant load relative to 40 and 75% maximal O₂ consumption (O_2 max). [¹³C]bicarbonate (0.0125 g/kg body wt) was administered as an intravenous bolus in each test. Respiratory mass spectrometry was used to derive the course of the end-tidal ¹³CO₂-to-¹²CO₂ ratio from the breath-by-breath data. Approximately 2 min after ¹³C administration, the washout curve could be fitted well by a two-exponential curve describing a two-compartment mammillary model. Immediately after administration of the bolus dose, an excess peak in the end-tidal ¹³CO₂-to-¹²CO₂ ratio appeared. This peak could not be included in the two-exponential fitting. The area under the first peak resulted in 3.8 ± 1.3% of the total [¹³C]bicarbonate dose at rest, 11.5 ± 2.9% at moderate exercise (40% O_2 max), and 16.9 ± 4.0% at intensive exercise (75% O_2 max). The first-pass effect had an increasing impact of up to about two-thirds of the lacking bicarbonate with higher exercise intensity. The "loss" of tracer via this first-pass effect must be considered when the results of studies with parenteral administration of [¹³C]bicarbonate are considered, especially when it is given as a bolus dose and during exercise.