In vivo measurements of pulmonary angiotensin-converting enzyme kinetics. I. Theory and error analysis.
We developed a procedure for measuring pulmonary angiotensin-converting enzyme kinetics with fluorine-18 fluorocaptopril and positron emission tomography (PET). The method is based on the application of a compartmental receptor model that represents the kinetics of two species of ligand, presumably the trans and cis conformers of captopril. The input function was characterized and includes corrections for the labeled metabolites of fluorocaptopril. Application of the procedure to lung time-activity data obtained with PET produced estimates of kinetic parameters demonstrating fast kinetics for one conformer and slower kinetics for the other. Simulation studies were performed to evaluate the sensitivity of the estimated parameters to errors in the model assumptions and in measured values for variables required for analysis of the PET data. Estimates for two of the kinetic parameters, the amount of perfused unbound functional enzyme normalized to regional lung volume and the association rate constant for the trans conformer, were relatively stable even with large errors in the input data, varying < 30% from true values for all perturbations. Thus, the procedure produces reliable estimates of the kinetics of the trans conformer of captopril as well as theoretical curves that are close to the observed data.
Markham
J
J
Institute for Biomedical Computing, Washington University Medical School, St. Louis, Missouri 63110, USA.
McCarthy
T J
TJ
Welch
M J
MJ
Schuster
D P
DP
D000818:Animals; D002216:Captopril / Q000493:pharmacokinetics; D003198:Computer Simulation; D004285:Dogs; D005462:Fluorine Radioisotopes; D007700:Kinetics; D008168:Lung / Q000000981:diagnostic imaging / Q000187:drug effects / Q000201:enzymology*; D008954:Models, Biological; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism*; D014055:Tomography, Emission-Computed
D005462:Fluorine Radioisotopes; D002216:Captopril; D007703:Peptidyl-Dipeptidase A