Breath tests with (13)C substrates.

Labeled (stable and radio) isotope compounds ((2)H, (3)H, (14)C, (13)C, (15)N) have been widely used as diagnostic probes in research laboratories for over 30 years in the fields of gastroenterology, hepatology, oncology, and nutrition, as well as pharmacokinetic studies in the development of drugs. (13)C stable isotope diagnostic probes are now being expanded in their scope, to provide precise evaluations of the presence or absence of etiologically significant changes in metabolism due to a specific disease or the lack of a specific enzyme. The concept exploits the use of the (13)C- label that is incorporated at the appropriate site into a selected substrate specifically designed for the targeted enzyme in a discrete metabolic pathway. The enzyme-substrate interaction results in the release of (13)CO(2) in the expired breath. The subsequent quantification of (13)CO(2) allows for the indirect determination of pharmacokinetics and the evaluation of enzyme activity. Breath tests, although non-invasive, have not been integrated routinely in clinical practice due to most of them requiring multiple breath sample collection over an extended time period. The use of area-under-the-curve (AUC) and percent-dose-recovery (PDR) parameters of breath tests to differentiate between controls and patients has been a huge barrier to implementing them into routine clinical practice due to time constraints on clinical staff. In order to get breath tests accepted in clinical practice as in vivo diagnostic tools, the tests need to be accurate with high sensitivity and specificity with a single time point breath collection post ingestion of a (13)C substrate. It is now incumbent on diagnostic test companies to invest capital for the development of promising single time point breath tests and getting regulatory board approval (FDA, EMEA), CPT codes and reimbursement. Following regulatory approvals, the breath tests would also need to be marketed aggressively by making physicians, patients, and insurance companies aware of the medical benefits to patients and lowering of healthcare costs. The diagnostic breath tests will enable physicians and patients to benefit from rapid, novel and non-invasive ways to detect enzyme deficiencies, to monitor the progress of disease severity or medication efficacy, to trace acquired and/or congenital metabolic defects, to study in vivo the pharmacokinetics of xenobiotics, and to optimize individually tailored treatment regimens for drugs with narrow therapeutic windows. The primary reason for publishing this special section on (13)C breath tests is to highlight some of the recent advances in the field of breath tests as well as to review the literature.