Performance of human mass balance studies with stable isotope-labeled drug and continuous flow isotope ratio mass spectrometry: A progress report

We propose performing human mass balance studies by administering stable isotope labeled (C-13 or N-15) drug and quantitating excess (above background) C-13 or N-15 in urine, serum, and feces by continuous flow-isotope ratio mass spectrometry (CF-IRMS). Theoretical calculations and empirical data (dynamic range, linearity, sensitivity, precision, accuracy) are presented to establish that commercially available CF-IRMS instruments can quantitate stable isotope labeled (one or two N-15 or C-13 labels) drug concentrations of 1.0 mu g/mL or greater in urine, serum (N-15), or feces. More than two C-13 labels may be necessary to quantitate 1.0 mu g/mL of drug in serum. Three volunteers received 650 mg of (NC2)-N-15-C-13- acetaminophen, and urine was collected for 72 hours. Percent of administered label recovered in urine from the three subjects was 97.4, 78.9, and 95.4 for C-13 and 90.3, 77.0, and 90.6 for N-15. Fecal recovery of label for one subject was 0.9% (C-13(2)) and 1.1% (N-15). Serum pharmacokinetic values obtain ed by counting C-13 or N-15 in one subject were as expected for acetaminophen. This method appears to be promising, and further validation is ongoing. (C)1998 The American College of Clinical Pharmacology.