Metabolism kinetics of beclomethasone propionate esters in human lung homogenates

Purpose. The purposes of this study were to characterize the kinetics of beclomethasone dipropionate (BDP) and its 17-monopropionate ester (17-BMP) in human lung 1000g supernatant (HLu) at 37 degrees C, and to analyze the interindividual variability in the metabolism of BDP in HLu. Methods. The concentrations of BDP and its metabolites were determined by HPLC with UV detection at 242 nm. Kinetics of BDP and 17-BMP decomposition were characterized by least-squares fitting of rate equations. Results. The active metabolite 17-BMP was rapidly formed following the incubation of BDP in HLu. Kinetics of BDP and 17-BMP in HLu were nonlinear owing to product inhibition and enzyme saturation. A model taking into account the product inhibition provides a kinetic basis for understanding the in vivo behavior of BDP and its metabolites in human lung. There was approximately a 3.5-fold difference in the initial half-life of BDP in HLu observed in seven subjects. Conclusions. An effective activation of BDP was demonstrated in HLu through the rapid formation of 17-BMP. Kinetics of BDP and 17-BMP in HLu were well characterized by the nonlinear kinetic model. Interindividual difference in the initial half-life of BDP was due mainly to esterase metabolizing activity rather than binding affinity.