Metabolism of beclomethasone dipropionate by cytochrome P450 3A enzymes.

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Roberts JK, Moore CD, Ward RM, Yost GS, Reilly CA

Metabolism of beclomethasone dipropionate by cytochrome P450 3A enzymes.

J Pharmacol Exp Ther. 2013 May;345(2):308-16. doi: 10.1124/jpet.112.202556. Epub 2013 Mar 19.

PubMed ID

23512537 [ View in PubMed

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Abstract

Inhaled glucocorticoids, such as beclomethasone dipropionate (BDP), are the mainstay treatment of asthma. However, approximately 30% of patients exhibit little to no benefit from treatment. It has been postulated that glucocorticoid resistance, or insensitivity, is attributable to individual differences in glucocorticoid receptor-mediated processes. It is possible that variations in cytochrome P450 3A enzyme-mediated metabolism of BDP may contribute to this phenomenon. This hypothesis was explored by evaluating the contributions of CYP3A4, 3A5, 3A7, and esterase enzymes in the metabolism of BDP in vitro and relating metabolism to changes in CYP3A enzyme mRNA expression via the glucocorticoid receptor in lung and liver cells. CYP3A4 and CYP3A5 metabolized BDP via hydroxylation ([M4] and [M6]) and dehydrogenation ([M5]) at similar rates; CYP3A7 did not metabolize BDP. A new metabolite [M6], formed by the combined action of esterases and CYP3A4 hydroxylation, was also characterized. To validate the results observed using microsomes and recombinant enzymes, studies were also conducted using A549 lung and DPX2 liver cells. Both liver and lung cells produced esterase-dependent metabolites [M1-M3], with [M1] correlating with CYP3A5 mRNA induction in A549 cells. Liver cells produced both hydroxylated and dehydrogenated metabolites [M4, M5, and M6], but lung cells produced only the dehydrogenated metabolite [M5]. These studies show that CYP3A4 and CYP3A5 metabolize BDP to inactive metabolites and suggest that differences in the expression or function of these enzymes in the lung and/or liver could influence BDP disposition in humans.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Beclomethasone dipropionate	Cytochrome P450 3A4	Protein	Humans	No	Substrate Inducer	Details
Beclomethasone dipropionate	Cytochrome P450 3A5	Protein	Humans	Unknown	Inducer	Details

Pharmaco-transcriptomics

Drug	Drug Groups	Gene	Gene ID	Change	Interaction	Chromosome
Beclomethasone dipropionate	Approved Investigational	CYP3A5	1577	upregulated	Beclomethasone results in increased expression of CYP3A5 mRNA	7q22.1