Breath tests based on the administration of a (13)C-labeled drug and subsequent monitoring of (13)CO2 in the breath (quantified as DOB - delta over baseline) liberated from the drug during hepatic CPY-dependent detoxification are important tools in liver function diagnostics. The capability of such breath tests to reliably indicate hepatic CYP performance is limited by the fact that (13)CO2 is not exclusively exhaled but also exchanged with other compartments of the body. In order to assess this bias caused by variations of individual systemic CO2 kinetics we administered intravenously the test drug (13)C-methacetin to 25 clinically liver-healthy individuals and monitored progress curves of DOB and the plasma concentration of (13)C-methacetin. Applying compartment modelling we estimated for each individual a set of kinetic parameters characterizing the time-dependent exchange of the drug and of CO2 with the liver and non-hepatic body compartments. This analysis revealed that individual variations in the kinetics of CO2 may account for up to 30% deviation of DOB curve parameters from their mean at otherwise identical (13)C-methacetin metabolization rates. In order to correct for this bias we introduced a novel detoxification score which ideally should be assessed from the DOB curve of a 2-step test ("2DOB") which is initialized with the injection of a standard dose of (13)C-labeled bicarbonate (in order to provide information on the actual CO2 status of the individual) followed by injection of the (13)C-labeled test drug (the common procedure). Computer simulations suggest that the predictive power of the proposed 2DOB breath test to reliably quantity the CYP-specific hepatic detoxification activity should be significantly higher compared to the conventional breath test.