Optimizing the erythromycin breath test for use in cancer patients

The erythromycin breath test (EBT) is a putative in vivo probe for drug met abolism by cytochrome P450 3A4 (CYP3A4). Because many anticancer drugs are metabolized by this system, we sought to further develop the EBT as a tool for predicting the clearance, in cancer patients, of drugs metabolized by C YP3A4. Sixteen adult patients with incurable cancer were studied. The EBT was perf ormed on day 1 and breath sampled after the i.v. injection of 4 mu Ci of C- 14-erythromycin. The breath (CO2)-C-14 flux (CERt) was estimated at 11 time points over 2 h. On day 2, the EBT was repeated midway through a 10-min in fusion of 100 mg of erythromycin lactobionate, and the plasma pharmacokinet ics of erythromycin were determined. The infusion of 100 mg of erythromycin did not modify the EBT results signi ficantly. The values of the conventional EBT parameter CER20 min obtained o n day 1 were comparable for most subjects (0.03-0.06% dose/min), with the e xception of an individual receiving the known CYP3A4 inducers dexamethasone and phenytoin who returned a value of 0.14% dose/min. There was no signifi cant correlation between any of the conventional EBT parameters and erythro mycin clearance. However, two parameters reflecting early emergence of brea th radioactivity (1/T-MAX and CER3 min/CERMAX) correlated significantly wit h erythromycin clearance (P = 0.005 and 0.006, respectively). Novel parameters derived from the EBT are significantly correlated with the clearance of erythromycin even in the presence of confounding factors, suc h as metastatic liver disease, altered protein binding, and comedication. T hese parameters may enable dose optimization of cytotoxics metabolized by C YP3A4.