Abstract
Purpose. The purposes of this study were to characterizethe kinetics of beclomethasone dipropionate (BDP) and its 17-monopropionateester (17-BMP) in human lung 1000g supernatant (HLu) at 37°C, and toanalyze the interindividual variability in the metabolism of BDP in HLu.
Methods. The concentrations of BDP and its metaboliteswere determined by HPLC with UV detection at 242 nm. Kinetics of BDP and17-BMP decomposition were characterized by least-squares fitting of rateequations.
Results. The active metabolite 17-BMP was rapidly formedfollowing the incubation of BDP in HLu. Kinetics of BDP and 17-BMP in HLuwere nonlinear owing to product inhibition and enzyme saturation. A modeltaking into account the product inhibition provides a kinetic basis forunderstanding 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 ofBDP in HLu observed in seven subjects.
Conclusions. An effective activation of BDP wasdemonstrated in HLu through the rapid formation of 17-BMP. Kinetics of BDPand 17-BMP in HLu were well characterized by the nonlinear kinetic model.Interindividual difference in the initial half-life of BDP was due mainly toesterase metabolizing activity rather than binding affinity.
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REFERENCES
J. B. Wilcox and G. S. Avery. Beclomethasone dipropionate corticosteroid inhaler: A preliminary report of its pharmacological properties and therapeutic efficacy in asthma. Drugs 6:84–93 (1973).
R. N. Brogden, R. C. Heel, T. M. Speight, and G. S. Avery. Beclomethasone dipropionate: A reappraisal of its pharmacodynamic properties and therapeutic efficacy after a decade of use in asthma and rhinitis. Drugs 28:99–126 (1984).
L. E. Martin, R. J. N. Tanner, T. J. H. Clark, and G. M. Cochrane. Absorption and metabolism of orally administered beclomethasone dipropionate. Clin. Pharmacol. Ther. 15:267–275 (1974).
P. Andersson and Å. Ryrfeldt. Biotransformation of the topical glucocorticoids budesonide and beclomethasone 17α,21-dipropionate in human liver and lung homogenate. J. Pharm. Pharmacol. 36:763–765 (1984).
G. Würthwein and P. Rohdewald. Activation of beclomethasone dipropionate by hydrolysis to beclomethasone-17-monopropionate. Biopharm. Drug Dispos. 11:381–394 (1990).
P. Rohdewald, N. Von Eiff, and G. Würthwein. Activation of beclomethasone dipropionate in bronchial secretion and receptor affinities and solubility of inhalationally administered glucocorticoids. Atemwegs Lungenkrankh. 16:79–84 (1990).
B. Davies. A comparison of beclomethasone dipropionate and budesonide in the treatment of asthma. Br. J. Clin. Pract. 47:87–93 (1993).
I. Pavord and A. Knox. Pharmacokinetic optimisation of inhaled steroid therapy in asthma. Clin. Pharmacokinet. 25:126–135 (1993).
P. Högger, U. Bonsmann, and P. Rohdewald. Efflux of glucocorticoids from human lung tissue to human plasma in vitro. Eur. Respir. J. 7(Suppl. 18):382s (1994).
J. B. Houston. Utility of in vitro drug metabolism data in predicting in vivo metabolic clearance. Biochem. Pharmacol. 47:1469–1479 (1994).
T. Iwatsubo, N. Hirota, T. Ooie, H. Suzuki, N. Shimada, K. Chiba, T. Ishizaki, C. E. Green, C. A. Tyson, and Y. Sugiyama. Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data. Pharmacol. Ther. 73:147–171 (1997).
B. T. Doumas, D. D. Bayse, R. J. Carter, T. Peters, Jr., and R. Schaffer. A candidate reference method for determination of total protein in serum. I. Development and validation. Clin. Chem. 27:1642–1650 (1981).
A. N. Martin. Kinetics. In A. N. Martin, P. Bustamante, and A. H. C. Chun (eds.), Physical Pharmacy: Physical Chemical Principles in the Pharmaceutical Sciences, Lea and Febiger, Philadelphia, PA, 1993, pp. 284–323.
T. Kokobu, E. Ueda, K. Nishimora, and N. Yoshida. Angiotensin I converting enzyme activity in pulmonary tissue of fetal and newborn rabbits. Experientia 33:1137–1138 (1977).
S. A. Stalcup, L. M. Pang, J. S. Lipset, C. E. Odya, T. L. Goodfriend, and R. B. Mellins. Gestational changes in pulmonary converting enzyme activity in the fetal rabbit. Circ. Res. 43:705 (1978).
J. B. Karlinsky and G. L. Snider. Animal models of emphysema. Am. Rev. Respir. Dis. 117:1109–1133 (1978).
T. R. Devereux and J. R. Fouts. Xenobiotic metabolism by alveolar Type II cells isolated from rabbit lung. Biochem. Pharmacol. 30:1231–1237 (1981).
G. E. R. Hook. The metabolic potential of the lungs. In C. F. George, D. G. Shand, and A. G. Renwick (eds.), Presystemic Drug Elimination, Butterworth Scientific, London, 1982, pp. 117–146.
C. L. Litterst, E. G. Mimnaugh, and T. E. Gram. Comparative alterations in extrahepatic drug metabolism by factors known to affect hepatic activity. Biochem. Pharmacol. 26:749–755 (1977).
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Foe, K., Cutler, D.J., Brown, K.F. et al. Metabolism Kinetics of Beclomethasone Propionate Esters in Human Lung Homogenates. Pharm Res 17, 1007–1012 (2000). https://doi.org/10.1023/A:1007591624451
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DOI: https://doi.org/10.1023/A:1007591624451