Abstract
The anti-inflammatory glucocorticosteroid beclomethasone dipropionate was found previously to degrade in human plasma at 37°C to yield beclomethasone 17-monopropionate, beclomethasone 21-monopropionate, and beclomethasone together with three unknown species, D-1, D-2, and D-3. In this paper, we report the isolation of D-2 and D-3 by preparative HPLC and the elucidation of their structures. Both products D-2 and D-3 exhibited UV bathochromic shifts relative to beclomethasone dipropionate of 9 nm. From the mass spectrometry and 1H-NMR data, it is concluded that D-2 and D-3 are formed from beclomethasone and beclomethasone 21-monopropionate, respectively, with the loss of hydrogen chloride and the formation of a 9,11-epoxide. Data for 1H-NMR methyl chemical shifts are used to show that the epoxide has the mechanistically more plausible 9β,11β configuration. Thus, D-2 is 9β,11β-epoxy-16β-methyl-1,4-pregnadiene-17α,21-diol-3,20-dione, and D-3 is its corresponding 21-propanoate. The various enzyme-catalyzed and nonenzyme-catalyzed reactions involved in the degradation of beclomethasone dipropionate in human plasma are discussed. A degradation scheme is proposed.
Footnotes
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Send reprint requests to: Prof. Kenneth F. Brown, Department of Pharmacy (A15), Science Road, The University of Sydney, NSW 2006, Australia.
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This work was presented in part at the Scientific Meeting of Australasian Pharmaceutical Science Association, Melbourne, VIC, on December 5–7, 1996.
- Abbreviations used are::
- BDP
- beclomethasone dipropionate
- 17-BMP
- beclomethasone 17-monopropionate
- 21-BMP
- beclomethasone 21-monopropionate
- BOH
- beclomethasone
- APCI
- atmospheric pressure chemical ionization
- LCMS
- liquid chromatography-mass spectrometry
- Received May 9, 1997.
- Accepted October 22, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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